{"gene":"KDM4C","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2006,"finding":"GASC1/JMJD2C (KDM4C) demethylates tri- and dimethylated lysine 9 on histone H3 (H3K9me3/me2) via a hydroxylation reaction requiring iron and alpha-ketoglutarate as cofactors. Ectopic expression decreases H3K9me3/me2 levels, increases H3K9me1, delocalizes HP1, and reduces heterochromatin in vivo.","method":"In vitro demethylase assay with iron/alpha-KG cofactors; ectopic expression in cells with chromatin analysis; HP1 delocalization assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic reconstitution with cofactor requirements established, validated in vivo by multiple orthogonal methods, highly cited foundational study","pmids":["16732293"],"is_preprint":false},{"year":2007,"finding":"Jmjd2c is positively regulated by Oct4 in embryonic stem cells. Jmjd2c depletion causes ES cell differentiation and reduces Nanog expression. Jmjd2c demethylates H3K9me3 at the Nanog promoter, preventing binding of transcriptional repressors HP1 and KAP1.","method":"RNAi knockdown; ChIP assay at Nanog promoter; gene expression analysis; ES cell differentiation assay","journal":"Genes & Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal ChIP, RNAi loss-of-function with defined cellular phenotype, replicated in subsequent studies","pmids":["17938240"],"is_preprint":false},{"year":2009,"finding":"Jmjd2c is recruited to the P2 promoter region of the Mdm2 oncogene, demethylates H3K9 there, and increases Mdm2 expression in a demethylase-activity-dependent manner, leading to reduction of p53 protein levels.","method":"ChIP assay; overexpression and siRNA knockdown; Western blot for p53 and Mdm2","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus loss/gain-of-function, single lab, two orthogonal methods","pmids":["19732750"],"is_preprint":false},{"year":2012,"finding":"JMJD2C selectively interacts with HIF-1α (but not HIF-2α) and is recruited by HIF-1α to hypoxia response elements of target genes. JMJD2C decreases H3K9me3 at these elements, enhancing HIF-1 binding and activating transcription of BNIP3, LDHA, PDK1, SLC2A1, LOXL2, and L1CAM. JMJD2C knockdown inhibits breast tumor growth and lung metastasis in mice.","method":"Co-immunoprecipitation; ChIP; knockdown with xenograft tumor model; gene expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP, in vivo xenograft with defined molecular mechanism, multiple orthogonal methods","pmids":["23129632"],"is_preprint":false},{"year":2013,"finding":"Jmjd2c depletion in mouse ESCs impairs differentiation and leads to a post-implantation epiblast-like arrest. Jmjd2c is re-distributed to lineage-specific enhancers during ESC priming. Loss of Jmjd2c abrogates G9a recruitment and destabilizes loading of mediator (Med1) and cohesin (Smc1a) at newly activated/poised enhancers, implicating Jmjd2c as a molecular scaffold for enhancer-protein complex assembly.","method":"Jmjd2c knockout ESCs; ChIP-seq; co-occupancy analysis; differentiation assays","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout ESC model, genome-wide ChIP-seq, multiple orthogonal methods in single rigorous study","pmids":["28087629"],"is_preprint":false},{"year":2013,"finding":"KDM4C binds to the β-catenin target gene JAG1 promoter and is required for β-catenin recruitment to JAG1 independently of H3K9 methylation status; this feed-forward mechanism drives colonosphere formation in colorectal cancer cells.","method":"ChIP; siRNA knockdown; colonosphere formation assay; microarray gene expression","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional knockdown, single lab, two orthogonal methods","pmids":["23698634"],"is_preprint":false},{"year":2013,"finding":"Jmjd2c and Jmjd2b have distinct genomic targets in ESCs: Jmjd2c uniquely targets Polycomb repressive complex (PRC) module sites and assists PRC2 in transcriptional repression, while Jmjd2b operates through the Core module. Both are required for induced pluripotent stem cell generation.","method":"RNAi screen; genome-wide ChIP-seq occupancy; iPSC reprogramming assay; double knockdown","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq, functional RNAi screen, multiple orthogonal methods in single rigorous study","pmids":["24361252"],"is_preprint":false},{"year":2014,"finding":"JMJD2C localizes to H3K4me3-positive transcription start sites via its double Tudor domain (TTD), which recognizes H3K4me3 but not H4K20me2/me3 in vitro—a binding specificity different from JMJD2A and JMJD2B Tudor domains. Depletion in KYSE150 carcinoma cells impairs proliferation and deregulates target genes involved in cell cycle progression, with modest effects on global H3K9me3 and H3K36me3.","method":"Jmjd2c knockout mice; ChIP-seq; in vitro Tudor domain binding assay; siRNA knockdown in carcinoma cells","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro domain binding assay, genome-wide ChIP-seq, knockout mouse, multiple orthogonal methods","pmids":["24396064"],"is_preprint":false},{"year":2014,"finding":"KDM4C is associated with mitotic chromatin, mediated by its C-terminal Tudor domains; the R919 residue on the proximal Tudor domain is critical for this mitotic chromatin association. Depletion or overexpression of KDM4C causes >3-fold increase in abnormal mitosis including misaligned chromosomes and anaphase bridges. A demethylase-dead mutant has no effect on chromosome segregation, implicating catalytic activity in mitotic fidelity.","method":"Live-cell imaging; immunofluorescence; point mutant overexpression; siRNA knockdown; mitotic error scoring","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiment, domain/point-mutant functional dissection, catalytic dead mutant control, defined mitotic phenotype","pmids":["24728997"],"is_preprint":false},{"year":2014,"finding":"KDM4C forms a complex with β-catenin in colon cancer cells (co-immunoprecipitation). KDM4C downregulation reduces growth, clonogenicity, and expression of FRA1, cyclin D1, and BCL2 in HCT-116 cells.","method":"Co-immunoprecipitation; siRNA knockdown; proliferation and clonogenic assays; Western blot","journal":"American Journal of Translational Research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP plus functional knockdown, single lab","pmids":["24936217"],"is_preprint":false},{"year":2013,"finding":"IP6K1-synthesized inositol pyrophosphate (IP7) interacts with JMJD2C and causes its dissociation from chromatin, increasing H3K9me3 levels; reduced IP7 (via IP6K1 RNAi or ip6k1-/- MEFs) leads to decreased H3K9me3 and increased H3K9ac, with downstream changes in JMJD2C target gene transcription.","method":"Co-immunoprecipitation; IP6K1 RNAi and knockout MEFs; chromatin fractionation; histone modification analysis; gene expression assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, genetic knockout model, two orthogonal methods, single lab","pmids":["24191012"],"is_preprint":false},{"year":2016,"finding":"The Tudor domain (TTD) of KDM4C recognizes H3K4me3 and this recognition stimulates KDM4C-mediated demethylation of H3K9me3 in cis on peptide and mononucleosome substrates, establishing a multivalent interaction mechanism that facilitates mutual exclusion of H3K4me3 and H3K9me3 marks.","method":"In vitro demethylase assay with peptide and mononucleosome substrates; quantitative TTD binding assays; kinetic analysis","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution on defined substrates, kinetic quantification, mechanistic mutagenesis-adjacent domain analysis","pmids":["26747609"],"is_preprint":false},{"year":2016,"finding":"KDM4C transcriptionally activates serine-glycine biosynthesis and amino acid transport genes by removing H3K9me3 from their promoters. This activity requires ATF4: KDM4C activates ATF4 transcription and physically interacts with ATF4 to co-target serine pathway genes, leading to increased intracellular amino acid levels.","method":"ChIP; co-immunoprecipitation; metabolomics; siRNA knockdown; gene expression analysis","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, Co-IP, metabolomics, and functional knockdown, multiple orthogonal methods in single study","pmids":["26774480"],"is_preprint":false},{"year":2015,"finding":"Jmjd2c directly associates with MyoD in vitro and in vivo, demethylates MyoD, and stabilizes MyoD by inhibiting G9a-dependent methylation-driven MyoD ubiquitination (through the Cul4/Ddb1/Dcaf1 pathway). Stabilized MyoD activates myogenic target genes; Jmjd2c also erases H3K9me3 at MyoD target gene promoters.","method":"GST pull-down; co-immunoprecipitation; in vitro demethylation assay; ubiquitination assay; myogenic conversion assay; ChIP","journal":"Biochimica et Biophysica Acta","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro pull-down plus Co-IP, enzymatic demethylation of non-histone substrate, ubiquitination mechanistic dissection, multiple orthogonal methods","pmids":["26149774"],"is_preprint":false},{"year":2015,"finding":"KDM4C binds to histones at the VE-cadherin promoter and is required for VE-cadherin expression and mouse ESC differentiation to endothelial cells; KDM4C depletion impairs capillary tube formation and vasculogenesis.","method":"ChIP; siRNA knockdown; endothelial differentiation assay; tube formation assay; zebrafish vasculogenesis model","journal":"Stem Cell Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional knockdown, in vivo zebrafish model, single lab","pmids":["26120059"],"is_preprint":false},{"year":2019,"finding":"JMJD2C reduces H3K9me3 and H3K36me3 at the MALAT1 promoter, upregulating MALAT1 expression, which activates the β-catenin signaling pathway and promotes colorectal cancer metastasis. JMJD2C protein translocates to the nucleus to execute this function.","method":"ChIP-PCR; luciferase reporter assay; siRNA knockdown/overexpression; Western blot; in vivo metastasis model","journal":"Journal of Experimental & Clinical Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, luciferase reporter, functional assays, single lab","pmids":["31665047"],"is_preprint":false},{"year":2019,"finding":"SUV39H1, JMJD2C, and SRC-1 form an interacting regulatory axis at the p66Shc promoter: SUV39H1 is the upstream effector orchestrating JMJD2C/SRC-1 recruitment. JMJD2C demethylates H3K9 at the p66Shc promoter, contributing to p66Shc transcription and ROS-driven endothelial dysfunction in obesity.","method":"ChIP; siRNA reprogramming in isolated endothelial cells and aortas; genetic manipulation in obese mice; ROS/NO measurement","journal":"European Heart Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, in vivo genetic models, mechanistic epistasis established, single lab","pmids":["29077881"],"is_preprint":false},{"year":2020,"finding":"KDM4C regulates ALKBH5 (m6A demethylase) expression by reducing H3K9me3 levels and increasing chromatin accessibility at the ALKBH5 locus, thereby promoting recruitment of MYB and Pol II. In AML, this axis drives leukemia stem cell maintenance via ALKBH5-dependent stabilization of AXL mRNA.","method":"ChIP; ATAC-seq; siRNA/shRNA knockdown; xenograft leukemia stem cell assays; RNA m6A analysis","journal":"Cell Stem Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, ATAC-seq, in vivo LSC functional assays, multiple orthogonal methods, rigorous controls","pmids":["32402251"],"is_preprint":false},{"year":2021,"finding":"USP9X deubiquitinates and stabilizes KDM4C protein. KDM4C upregulates TGF-β2 expression by directly reducing H3K9me3 at the TGF-β2 promoter, activating Smad/ATM/Chk2 signaling and conferring radioresistance in lung cancer. Depletion of USP9X destabilizes KDM4C and impairs TGF-β2/Smad signaling.","method":"Tandem affinity purification; co-immunoprecipitation; ChIP; ubiquitination assay; siRNA knockdown; xenograft model","journal":"Cell Death and Differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — TAP identification of binding partner, Co-IP, ChIP, in vivo xenograft, multiple orthogonal methods","pmids":["33558705"],"is_preprint":false},{"year":2021,"finding":"KDM4C suppresses the pro-apoptotic functions of p53 by demethylating p53 at K372me1, which is pivotal for the stability of chromatin-bound p53. KDM4C also binds to the c-Myc promoter and induces c-Myc expression. A catalytic dead KDM4C mutant fails to rescue proliferation after knockdown.","method":"Catalytic dead mutant rescue experiment; ChIP; Western blot; apoptosis assay; in vitro and in vivo glioblastoma models","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — catalytic dead mutant used, ChIP for c-Myc promoter, single lab, multiple methods","pmids":["33462212"],"is_preprint":false},{"year":2021,"finding":"UHRF1 recruits KDM4C to the CDC6 promoter, where KDM4C demethylates H3K9me2/3 to convert heterochromatin to a permissive state, enabling androgen receptor occupancy and CDC6 transcription, contributing to anti-androgen resistance in prostate cancer.","method":"ChIP; co-immunoprecipitation; siRNA knockdown; xenograft model","journal":"Cancer Letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus Co-IP, functional knockdown, single lab","pmids":["34265399"],"is_preprint":false},{"year":2019,"finding":"KDM3A and KDM4C transcriptionally activate condensin components NCAPD2 and NCAPG2 via H3K9 demethylation, leading to heterochromatin reorganization during MSC senescence. Suppression of KDM4C aggravates DNA damage response and cellular senescence; overexpression promotes heterochromatin reorganization and blunts DNA damage.","method":"siRNA/shRNA knockdown; overexpression; ChIP; DNA damage assays; Kdm3a-/- mouse model","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, genetic knockout mouse, functional assays, single lab","pmids":["31704649"],"is_preprint":false},{"year":2022,"finding":"KDM4C inhibition increases H3K36me3 binding at the CXCL10 promoter, inducing CXCL10 transcription and enhancing CD8+ T cell-mediated antitumor immunity in lung cancer. Genetic or pharmacological KDM4C inhibition specifically increased CD8+ T cell infiltration and activation.","method":"ChIP-PCR; RNA-seq; flow cytometry; in vivo mouse tumor model; pharmacological inhibitor SD70","journal":"Journal for Immunotherapy of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, RNA-seq, in vivo model, single lab, multiple methods","pmids":["35121645"],"is_preprint":false},{"year":2018,"finding":"KDM4A and KDM4C interact with NF-κB p65 and co-target the Wdr5 locus (a MLL complex member promoting H3K4 methylation), upregulating cell cycle inhibitors Cdkn2c and Cdkn3 in activated B cells. ChIP-seq revealed NF-κB p65 as a binding partner.","method":"ChIP-seq; de novo motif analysis; co-immunoprecipitation; siRNA knockdown; B cell proliferation assay","journal":"Nucleic Acids Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, Co-IP, functional knockdown, single lab","pmids":["29718303"],"is_preprint":false},{"year":2014,"finding":"Substrate- and cofactor-independent cyclic peptide inhibitors of KDM4C were identified by phage display screening. Hydrogen/deuterium exchange mass spectrometry showed these peptides interact with KDM4C at surface regions remote from the active site, providing a new mode of inhibition.","method":"Phage display screening; H/D exchange mass spectrometry; in vitro inhibition assays; peptide SAR","journal":"ACS Chemical Biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical assays, HD-exchange MS structural characterization, single lab","pmids":["25014588"],"is_preprint":false},{"year":2021,"finding":"GASC1/KDM4C transcriptionally represses FBXO42 (a ROCK2 ubiquitin ligase) via its demethylase activity, thereby preventing K63-linked poly-ubiquitination and degradation of ROCK2, promoting hepatocellular carcinoma growth.","method":"siRNA knockdown; ubiquitination assay; ChIP; demethylase inhibitor treatment; xenograft model","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, ubiquitination assay, functional knockdown, single lab","pmids":["33692332"],"is_preprint":false},{"year":2023,"finding":"BACH1 binds to the KDM4C promoter to transcriptionally activate KDM4C expression. KDM4C in turn occupies the COX2 gene promoter and promotes COX2 expression by eliminating H3K9me3, contributing to ferroptosis in neuroblastoma and cerebral ischemia-reperfusion injury.","method":"ChIP; siRNA knockdown; overexpression rescue; in vivo MCAO mouse model","journal":"The European Journal of Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, genetic manipulation, in vivo model, single lab","pmids":["37161649"],"is_preprint":false},{"year":2022,"finding":"KDM4C loss in JAK2-mutated cells results in alterations of H3K9me3 target gene expression, loss of cell competition, reduced proliferation, and induction of cellular senescence, establishing KDM4C as a selective genetic dependency in JAK2-mutated myeloid neoplasms.","method":"Genetic inactivation (CRISPR); xenograft models; histone methylation analysis; gene expression; senescence assays","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR knockout, in vivo xenograft, multiple functional readouts, single lab","pmids":["35654819"],"is_preprint":false},{"year":2023,"finding":"NFE2 directly activates JMJD2C transcription as a target gene. Loss of JMJD2C selectively impairs proliferation of JAK2V617F mutated cells, linking NFE2-driven leukemogenesis to KDM4C upregulation.","method":"Chromatin immunoprecipitation; shRNA knockdown; proliferation assays in JAK2V617F and transgenic mouse models","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating NFE2 binding, functional knockdown, single lab","pmids":["36709354"],"is_preprint":false},{"year":2025,"finding":"In KDM4C-amplified basal breast cancer, KDM4C inhibition does not primarily alter H3K9me3/H3K36me3 but instead causes methylation of GRHL2 at K453, which recruits cathepsin L (CTSL) to chromatin. CTSL then cleaves histone H3, decreasing glutamate-cysteine ligase expression and increasing reactive oxygen species. CTSL deletion rescues KDM4C-loss-mediated tumor suppression.","method":"CRISPR KO; proteomics; chromatin fractionation; CTSL activity assays; rescue experiments; transcriptomic analysis","journal":"Nature Genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods, genetic rescue, identifies non-canonical mechanism distinct from H3K9/36 demethylation, rigorous controls","pmids":["40457074"],"is_preprint":false},{"year":2026,"finding":"KDM4C interacts with SIRT1 via its Tudor reader domain (identified by proximity labeling). KDM4C loss reduces phospho-ERK in KRAS-mutant PDAC cells; mechanistically, KDM4C-SIRT1 interaction represses DUSP2 (an ERK-inactivating phosphatase), sustaining ERK signaling. CRISPR deletion of KDM4C reduces proliferation and improves survival in orthotopic PDAC models.","method":"Proximity labeling (BioID); CRISPR/Cas9 deletion; transcriptomic and proteomic analysis; in vivo orthotopic allograft model; phospho-ERK measurement","journal":"Cancer Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity labeling for interaction, CRISPR KO with in vivo validation, mechanistic pathway placement, single lab","pmids":["41490602"],"is_preprint":false},{"year":2019,"finding":"JMJD2C promotes esophageal squamous cell carcinoma stemness by demethylating H3K9me2/me3 at the NOTCH1 promoter, increasing NOTCH1 expression. Blockade of GASC1 increases NOTCH1 promoter H3K9me2/me3 and decreases NOTCH1 and ALDHbri+ cancer stem cell properties; NOTCH1 overexpression rescues these effects.","method":"ChIP; siRNA/shRNA knockdown; lentiviral overexpression rescue; ALDH+ cell sorting; in vivo xenograft","journal":"Journal of Oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with rescue experiment, in vivo model, single lab","pmids":["31031809"],"is_preprint":false},{"year":2015,"finding":"KDM4C demethylase activity is required for expression of FGF2 in osteosarcoma; GST pull-down showed JMJD2C interacts with FGF2 protein.","method":"GST pull-down; siRNA knockdown; Western blot; RT-PCR","journal":"Medical Oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single GST pull-down, single lab, limited mechanistic follow-up","pmids":["25636512"],"is_preprint":false},{"year":2024,"finding":"KDM4C reduces H3K9me3 at the ALKBH5 promoter to upregulate ALKBH5 expression; ALKBH5 then demethylates snail1 mRNA m6A modification to reduce its stability, thereby inhibiting liver fibrosis. ChIP-qPCR confirmed KDM4C binding and H3K9me3 reduction at the ALKBH5 promoter.","method":"ChIP-qPCR; overexpression/knockdown; RNA m6A quantification; in vivo CCl4 fibrosis model; Western blot","journal":"Journal of Digestive Diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, m6A analysis, in vivo model, single lab","pmids":["38938016"],"is_preprint":false},{"year":2025,"finding":"KDM4C interacts with GATA1 (confirmed by immunoprecipitation and docking) and co-regulates ferrochelatase (FECH) in heme metabolism in head and neck squamous cell carcinoma. FECH overexpression rescues cell migration and invasion suppressed by KDM4C or GATA1 knockdown.","method":"Co-immunoprecipitation; molecular docking; RNA-seq; CUT&Tag-seq; siRNA knockdown; zebrafish and mouse xenograft models","journal":"Cellular and Molecular Life Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, genome-wide CUT&Tag, rescue experiment, in vivo models, single lab","pmids":["40259045"],"is_preprint":false},{"year":2025,"finding":"Jmjd2c and SOX2 proteins physically interact with each other (Co-IP and GST pull-down confirmed); Jmjd2c is required for SOX2 expression in ALDHbri+ lung squamous cancer stem cells, and Jmjd2c-SOX2 double silencing has enhanced tumor suppression relative to either alone.","method":"Co-immunoprecipitation; GST pull-down; shRNA knockdown; tumor xenograft model","journal":"Cancer Biology & Therapy","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal Co-IP and pull-down confirming interaction, functional knockdown, single lab","pmids":["38975736"],"is_preprint":false},{"year":2025,"finding":"KDM4C overexpression upregulates ApoE expression in mouse hippocampal neural stem cells, promoting their proliferation; ApoE knockdown mitigates this proliferative effect, placing ApoE downstream of KDM4C.","method":"Lentiviral overexpression; RNA-seq; BrdU/Ki-67 staining; ApoE siRNA knockdown","journal":"FASEB Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — lentiviral overexpression, RNA-seq, functional rescue by ApoE knockdown, single lab","pmids":["38421303"],"is_preprint":false},{"year":2025,"finding":"In preeclampsia, KDM4C reduces H3K9me3 at the NFATc4 locus, increasing NFATc4 expression. NFATc4 then inhibits β-catenin nuclear translocation by binding Dishevelled (Dvl), disrupting Wnt/β-catenin signaling and suppressing trophoblast proliferation and migration.","method":"ChIP; siRNA overexpression/knockdown; co-immunoprecipitation; in vivo L-NAME-induced PE rat model; immunohistochemistry","journal":"International Journal of Biological Macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, Co-IP, in vivo model, mechanistic pathway placement, single lab","pmids":["40716534"],"is_preprint":false},{"year":2025,"finding":"Fumarate accumulation in FH-deficient renal cancer cells competitively inhibits KDM4C activity (by competing with α-ketoglutarate), leading to elevated H3K36me3 at target loci, activation of IL-6/JAK/STAT3 signaling, and increased CXCL10 and PD-L1 expression. In vitro and in vivo experiments confirmed fumarate's inhibitory effect on KDM4C.","method":"In vitro KDM4C activity assay with fumarate; ChIP-qPCR; siRNA knockdown; in vivo FH-knockdown models; RNA-seq","journal":"British Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro enzyme inhibition assay, ChIP, in vivo models, single lab","pmids":["40975760"],"is_preprint":false},{"year":2025,"finding":"KDM4C overexpression in glioblastoma cells reduces IR-induced DNA damage response and apoptosis; a catalytic inhibitor (SD70) reverses these effects. KDM4C overexpression causes broad transcriptional remodeling after irradiation, reducing radiosensitivity.","method":"KDM4C overexpression; clonogenic survival assay; DNA damage assay; apoptosis analysis; pharmacological inhibitor SD70; in vivo xenograft","journal":"International Journal of Radiation Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function plus pharmacological inhibition, in vivo xenograft, defined phenotype, single lab","pmids":["40711862"],"is_preprint":false},{"year":2025,"finding":"AVN A (Avenanthramide A) directly binds to the S198 site of KDM4C, promoting its degradation, thereby increasing H3K9me3 occupancy at the MIR17HG promoter, blocking MIR17HG transcription and derepressing Bim expression in colorectal cancer.","method":"Molecular-protein docking; cellular thermal shift assay (CETSA); ChIP; dual luciferase reporter; CRC organoids; Apc mouse model","journal":"Acta Pharmaceutica Sinica B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CETSA for direct binding, ChIP for mechanistic effect, in vivo models, single lab","pmids":["39807336"],"is_preprint":false},{"year":2023,"finding":"Structural variants in KDM4C result in loss-of-function in B-cell lymphomas. Functional reconstitution studies in lymphoma cell lines provided evidence that KDM4C can act as a tumor suppressor in this context.","method":"Whole genome sequencing; RNA-seq; functional reconstitution in cell lines; focal homozygous deletion identification","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reconstitution in cell lines, genomic and transcriptomic integration, single lab","pmids":["35522148"],"is_preprint":false},{"year":2011,"finding":"Enzymatic characterization of KDM4C demonstrates selectivity for H3K9me3 substrate; inhibition studies with 2,4-dicarboxypyridine and (R)-N-oxalyl-O-benzyltyrosine showed significant selectivity between KDM4C and KDM6A despite similar active site topologies.","method":"In vitro enzyme kinetics; inhibitor selectivity assay","journal":"FEBS Letters","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic characterization with kinetic measurements, single lab","pmids":["21575637"],"is_preprint":false},{"year":2025,"finding":"KDM4C inhibition in DLBCL cells causes epigenomic rewiring of heterochromatin; KDM4 demethylases associate with KRAB zinc finger protein ZNF587, and their enzymatic inhibition leads to DNA replication stress and DNA damage-induced cGAS-STING activation.","method":"Phenotypic screen; biochemical interaction analysis; cGAS-STING activation assay; high-throughput small molecule screen with nucleosome substrates","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2–3 / Weak — preprint, biochemical interaction, phenotypic screen, not yet peer-reviewed","pmids":[],"is_preprint":true}],"current_model":"KDM4C (GASC1/JMJD2C) is a Jumonji-C domain histone lysine demethylase that removes di- and tri-methyl marks from H3K9 and H3K36 via an iron- and alpha-ketoglutarate-dependent hydroxylation reaction; it localizes to H3K4me3-positive transcription start sites through its Tudor domain (which stimulates catalysis in cis), associates with mitotic chromatin via Tudor domain residue R919 to regulate chromosome segregation, acts as a transcriptional co-activator by interacting with partners including HIF-1α, ATF4, β-catenin, and NF-κB p65, can demethylate non-histone substrates such as MyoD-K372 to control protein stability, is stabilized by deubiquitinase USP9X, and in specific contexts (KDM4C-amplified basal breast cancer) drives tumor suppression upon loss by triggering GRHL2 methylation-dependent cathepsin L histone H3 cleavage rather than through its canonical H3K9/H3K36 demethylase activity."},"narrative":{"mechanistic_narrative":"KDM4C (GASC1/JMJD2C) is a Jumonji-C domain histone lysine demethylase that erases di- and tri-methyl marks from H3K9 (and H3K36) through an iron- and alpha-ketoglutarate-dependent hydroxylation reaction, thereby converting repressive heterochromatin into transcriptionally permissive chromatin and displacing HP1 [PMID:16732293]. Its substrate engagement is guided by a double Tudor domain that recognizes H3K4me3 at transcription start sites and stimulates H3K9me3 demethylation in cis, enforcing mutual exclusion of the two marks [PMID:24396064, PMID:26747609]; the Tudor domain also tethers KDM4C to mitotic chromatin via residue R919, where catalytic activity is required for faithful chromosome segregation [PMID:24728997]. Through these activities KDM4C functions as a transcriptional co-activator recruited by sequence-specific factors—including HIF-1α, ATF4, β-catenin, and NF-κB p65—to demethylate H3K9 at target promoters and enhancers and activate gene programs governing hypoxia, amino-acid metabolism, proliferation, and stem-cell identity [PMID:23129632, PMID:26774480, PMID:28087629, PMID:29718303]. In pluripotency, it is an Oct4-induced regulator that demethylates the Nanog promoter and acts as a scaffold for enhancer assembly, and it partitions distinct genomic targets from KDM4B during reprogramming [PMID:17938240, PMID:28087629, PMID:24361252]. KDM4C activity extends to non-histone substrates: it demethylates and stabilizes MyoD by blocking G9a-driven ubiquitination [PMID:26149774] and demethylates p53-K372me1 to restrain its pro-apoptotic function [PMID:33462212]. The enzyme is stabilized by the deubiquitinase USP9X [PMID:33558705] and its catalysis is tuned by metabolite levels, being inhibited by inositol pyrophosphate (IP7) and by fumarate competing with alpha-ketoglutarate [PMID:24191012, PMID:40975760]. Across diverse cancers KDM4C behaves predominantly as an oncogenic dependency driving metastasis, stemness, and therapy resistance [PMID:23129632, PMID:32402251, PMID:31031809], but it can act as a tumor suppressor whose loss is selected for in B-cell lymphoma [PMID:35522148], and in KDM4C-amplified basal breast cancer its inhibition triggers a non-canonical, demethylase-independent program in which GRHL2 methylation recruits cathepsin L to cleave histone H3 and elevate reactive oxygen species [PMID:40457074].","teleology":[{"year":2006,"claim":"Established the founding biochemical identity of KDM4C: that it is an iron/alpha-ketoglutarate-dependent enzyme capable of erasing the repressive H3K9me3/me2 marks, defining a new mechanism for active heterochromatin removal.","evidence":"In vitro demethylase assay with defined cofactors plus ectopic expression with HP1 delocalization in cells","pmids":["16732293"],"confidence":"High","gaps":["Did not resolve how the enzyme is recruited to specific loci","Genome-wide target spectrum not defined"]},{"year":2007,"claim":"Placed KDM4C in the pluripotency network by showing it is an Oct4-induced demethylase that activates Nanog, answering how H3K9 demethylation maintains stem-cell self-renewal.","evidence":"RNAi knockdown, ChIP at Nanog promoter, and ES cell differentiation assays","pmids":["17938240"],"confidence":"High","gaps":["Direct versus indirect recruitment to Nanog promoter not dissected","Did not address non-histone roles"]},{"year":2011,"claim":"Quantified KDM4C substrate selectivity for H3K9me3 and demonstrated inhibitor discrimination from related Jumonji enzymes despite shared active-site topology, establishing it as a tractable selective target.","evidence":"In vitro enzyme kinetics and inhibitor selectivity assays","pmids":["21575637"],"confidence":"Medium","gaps":["Selectivity tested against a single comparator (KDM6A)","No cellular validation of inhibitor selectivity"]},{"year":2014,"claim":"Resolved the recruitment logic of KDM4C, showing its double Tudor domain reads H3K4me3 (distinct from KDM4A/B specificity) to position the enzyme at active transcription start sites.","evidence":"In vitro Tudor binding assays, ChIP-seq, knockout mice, and siRNA in carcinoma cells","pmids":["24396064"],"confidence":"High","gaps":["Modest global H3K9me3/H3K36me3 changes left the catalytic contribution at most loci unclear","Did not connect TSS binding to catalysis mechanistically"]},{"year":2014,"claim":"Extended KDM4C function beyond transcription to mitotic fidelity, mapping mitotic chromatin association to Tudor residue R919 and showing catalytic activity is required to prevent chromosome missegregation.","evidence":"Live-cell imaging, point-mutant and catalytic-dead overexpression, siRNA, and mitotic error scoring","pmids":["24728997"],"confidence":"High","gaps":["The relevant mitotic substrate or chromatin region was not identified","How R919 binding couples to catalysis during mitosis unknown"]},{"year":2016,"claim":"Provided the mechanistic link between Tudor reading and catalysis, showing H3K4me3 recognition stimulates in-cis H3K9me3 demethylation, explaining mutual exclusion of the two marks.","evidence":"In vitro demethylase assays on peptide and mononucleosome substrates with kinetic and TTD-binding quantification","pmids":["26747609"],"confidence":"High","gaps":["In-cis stimulation not validated on native polynucleosome arrays in cells","Quantitative contribution to genome-wide demethylation not measured"]},{"year":2013,"claim":"Defined KDM4C as a transcription-factor-recruited co-activator, showing HIF-1α (not HIF-2α) tethers it to hypoxia response elements to demethylate H3K9 and drive a pro-metastatic gene program.","evidence":"Reciprocal Co-IP, ChIP, gene expression, and knockdown xenograft/metastasis models","pmids":["23129632"],"confidence":"High","gaps":["Determinants of HIF-1α versus HIF-2α selectivity not defined","Whether catalysis is strictly required at all HRE targets not established"]},{"year":2013,"claim":"Revealed a scaffolding role independent of and complementary to catalysis, showing KDM4C is needed to load G9a, Mediator, and cohesin at priming enhancers, and partitions targets from KDM4B during reprogramming.","evidence":"Knockout ESCs, ChIP-seq co-occupancy, RNAi screen, and iPSC reprogramming assays","pmids":["28087629","24361252"],"confidence":"High","gaps":["Direct protein contacts mediating scaffold assembly not mapped","Catalytic versus structural contributions at enhancers not separated"]},{"year":2015,"claim":"Demonstrated KDM4C acts on non-histone substrates and controls protein stability, demethylating MyoD to block G9a-driven ubiquitination and stabilize it.","evidence":"GST pull-down, Co-IP, in vitro demethylation, ubiquitination, and myogenic conversion assays","pmids":["26149774"],"confidence":"High","gaps":["Demethylated MyoD residue(s) not precisely defined in the synthesis","Generality of non-histone demethylation to other lineage factors unknown"]},{"year":2016,"claim":"Connected KDM4C to metabolic gene control, showing it activates and partners with ATF4 to upregulate serine-glycine biosynthesis and amino-acid transport, raising intracellular amino-acid levels.","evidence":"ChIP, Co-IP, metabolomics, and siRNA knockdown","pmids":["26774480"],"confidence":"High","gaps":["Whether ATF4 interaction is direct or chromatin-templated not resolved","Feedback between metabolite availability and KDM4C catalysis not tested here"]},{"year":2020,"claim":"Positioned KDM4C upstream of RNA m6A regulation, showing it opens chromatin at the ALKBH5 locus to drive leukemia stem-cell maintenance, integrating histone and RNA epigenetic layers.","evidence":"ChIP, ATAC-seq, shRNA, xenograft LSC assays, and m6A analysis","pmids":["32402251"],"confidence":"High","gaps":["Direct transcription factors recruiting KDM4C to the ALKBH5 locus only partly defined","Whether the same axis operates outside AML not addressed here"]},{"year":2021,"claim":"Identified post-translational control of KDM4C abundance, showing the deubiquitinase USP9X stabilizes it to sustain TGF-β2/Smad signaling and radioresistance.","evidence":"Tandem affinity purification, Co-IP, ubiquitination assay, ChIP, and xenografts","pmids":["33558705"],"confidence":"High","gaps":["Ubiquitin ligase opposing USP9X on KDM4C not identified","Lysine residues ubiquitinated on KDM4C not mapped"]},{"year":2021,"claim":"Showed KDM4C restrains tumor suppression by demethylating p53-K372me1 while activating c-Myc, broadening its non-histone substrate repertoire to a key tumor suppressor.","evidence":"Catalytic-dead rescue, ChIP, apoptosis assays, and glioblastoma models","pmids":["33462212"],"confidence":"Medium","gaps":["Single-lab study without independent confirmation of p53-K372 demethylation","Direct enzyme-substrate kinetics on p53 not reported"]},{"year":2025,"claim":"Uncovered a demethylase-independent, context-specific tumor-suppressive vulnerability, showing that in KDM4C-amplified basal breast cancer its inhibition methylates GRHL2-K453, recruiting cathepsin L to cleave histone H3 and elevate ROS.","evidence":"CRISPR KO, proteomics, chromatin fractionation, CTSL activity assays, and genetic rescue","pmids":["40457074"],"confidence":"High","gaps":["Enzyme responsible for GRHL2-K453 methylation upon KDM4C loss not pinned down","Generalizability beyond KDM4C-amplified basal context unknown"]},{"year":2025,"claim":"Demonstrated metabolite-driven regulation of KDM4C, showing fumarate competes with alpha-ketoglutarate to inhibit catalysis, raising H3K36me3 and activating IL-6/JAK/STAT3 and immune-checkpoint gene expression in FH-deficient cancer.","evidence":"In vitro activity assay with fumarate, ChIP-qPCR, RNA-seq, and FH-knockdown models","pmids":["40975760"],"confidence":"Medium","gaps":["Quantitative selectivity of fumarate inhibition among KDM4 paralogs not established","Single-lab finding awaiting independent confirmation"]},{"year":null,"claim":"It remains unresolved when KDM4C acts as an oncogenic dependency versus a tumor suppressor, and what dictates the switch between its canonical H3K9/H3K36 demethylase activity and non-canonical catalytic-independent functions.","evidence":"No single study in the corpus reconciles the opposing context-dependent roles","pmids":[],"confidence":"Low","gaps":["No unifying model for context-dependent oncogene/tumor-suppressor behavior","Determinants selecting histone versus non-histone substrates not defined","In vivo physiological (non-cancer) functions largely uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[13,19]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,42]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[7,11]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,12,23]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,15]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,8]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,7,11]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,3,12]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,4,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,17,29]}],"complexes":[],"partners":["HIF1A","ATF4","CTNNB1","RELA","MYOD1","USP9X","SIRT1","GATA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H3R0","full_name":"Lysine-specific demethylase 4C","aliases":["Gene amplified in squamous cell carcinoma 1 protein","GASC-1 protein","JmjC domain-containing histone demethylation protein 3C","Jumonji domain-containing protein 2C","[histone H3]-trimethyl-L-lysine(9) demethylase 4C"],"length_aa":1056,"mass_kda":120.0,"function":"Histone demethylase that specifically demethylates 'Lys-9' and 'Lys-36' residues of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-4', H3 'Lys-27' nor H4 'Lys-20'. Demethylates trimethylated H3 'Lys-9' and H3 'Lys-36' residue, while it has no activity on mono- and dimethylated residues. Demethylation of Lys residue generates formaldehyde and succinate","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9H3R0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KDM4C","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KDM4C","total_profiled":1310},"omim":[{"mim_id":"605469","title":"LYSINE DEMETHYLASE 4C; KDM4C","url":"https://www.omim.org/entry/605469"},{"mim_id":"147700","title":"ISOCITRATE DEHYDROGENASE, NADP(+), 1; IDH1","url":"https://www.omim.org/entry/147700"},{"mim_id":"147650","title":"ISOCITRATE DEHYDROGENASE, NADP(+), 2; IDH2","url":"https://www.omim.org/entry/147650"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KDM4C"},"hgnc":{"alias_symbol":["GASC1","KIAA0780","TDRD14C"],"prev_symbol":["JMJD2C"]},"alphafold":{"accession":"Q9H3R0","domains":[{"cath_id":"2.60.120.650","chopping":"18-359","consensus_level":"high","plddt":93.5744,"start":18,"end":359},{"cath_id":"3.30.40.10","chopping":"629-655_681-696_707-866","consensus_level":"high","plddt":86.0905,"start":629,"end":866},{"cath_id":"3.10.330.70","chopping":"884-1018","consensus_level":"high","plddt":80.6297,"start":884,"end":1018}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H3R0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H3R0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H3R0-F1-predicted_aligned_error_v6.png","plddt_mean":71.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KDM4C","jax_strain_url":"https://www.jax.org/strain/search?query=KDM4C"},"sequence":{"accession":"Q9H3R0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H3R0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H3R0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H3R0"}},"corpus_meta":[{"pmid":"16732293","id":"PMC_16732293","title":"The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3.","date":"2006","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/16732293","citation_count":591,"is_preprint":false},{"pmid":"17938240","id":"PMC_17938240","title":"Jmjd1a and Jmjd2c histone H3 Lys 9 demethylases regulate self-renewal in embryonic stem cells.","date":"2007","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/17938240","citation_count":416,"is_preprint":false},{"pmid":"32402251","id":"PMC_32402251","title":"Leukemogenic Chromatin Alterations Promote AML Leukemia Stem Cells via a KDM4C-ALKBH5-AXL Signaling Axis.","date":"2020","source":"Cell stem cell","url":"https://pubmed.ncbi.nlm.nih.gov/32402251","citation_count":219,"is_preprint":false},{"pmid":"23129632","id":"PMC_23129632","title":"Histone demethylase JMJD2C is a coactivator for hypoxia-inducible factor 1 that is required for breast cancer progression.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23129632","citation_count":199,"is_preprint":false},{"pmid":"10987278","id":"PMC_10987278","title":"Identification of a novel gene, GASC1, within an amplicon at 9p23-24 frequently detected in esophageal cancer cell lines.","date":"2000","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/10987278","citation_count":198,"is_preprint":false},{"pmid":"19784073","id":"PMC_19784073","title":"Genomic amplification and oncogenic properties of the GASC1 histone demethylase gene in breast cancer.","date":"2009","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/19784073","citation_count":164,"is_preprint":false},{"pmid":"26774480","id":"PMC_26774480","title":"KDM4C and ATF4 Cooperate in Transcriptional Control of Amino Acid Metabolism.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26774480","citation_count":132,"is_preprint":false},{"pmid":"24361252","id":"PMC_24361252","title":"Distinct and combinatorial functions of Jmjd2b/Kdm4b and Jmjd2c/Kdm4c in mouse embryonic stem cell identity.","date":"2013","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/24361252","citation_count":105,"is_preprint":false},{"pmid":"18927281","id":"PMC_18927281","title":"Mucosa-associated lymphoid tissue lymphoma: novel translocations including rearrangements of ODZ2, JMJD2C, and CNN3.","date":"2008","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/18927281","citation_count":93,"is_preprint":false},{"pmid":"33558705","id":"PMC_33558705","title":"USP9X-mediated KDM4C deubiquitination promotes lung cancer radioresistance by epigenetically inducing TGF-β2 transcription.","date":"2021","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/33558705","citation_count":76,"is_preprint":false},{"pmid":"16737911","id":"PMC_16737911","title":"Molecular cytogenetic characterization of a metastatic lung sarcomatoid carcinoma: 9p23 neocentromere and 9p23-p24 amplification including JAK2 and JMJD2C.","date":"2006","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/16737911","citation_count":73,"is_preprint":false},{"pmid":"19696013","id":"PMC_19696013","title":"The histone demethylase JMJD2C is stage-specifically expressed in preimplantation mouse embryos and is required for embryonic development.","date":"2009","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/19696013","citation_count":68,"is_preprint":false},{"pmid":"24396064","id":"PMC_24396064","title":"The demethylase JMJD2C localizes to H3K4me3-positive transcription start sites and is dispensable for embryonic development.","date":"2014","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/24396064","citation_count":66,"is_preprint":false},{"pmid":"30537731","id":"PMC_30537731","title":"circZMYM2 Competed Endogenously with miR-335-5p to Regulate JMJD2C in Pancreatic Cancer.","date":"2018","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30537731","citation_count":62,"is_preprint":false},{"pmid":"24191012","id":"PMC_24191012","title":"Inositol pyrophosphates regulate JMJD2C-dependent histone demethylation.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24191012","citation_count":60,"is_preprint":false},{"pmid":"24936217","id":"PMC_24936217","title":"Pro-growth role of the JMJD2C histone demethylase in HCT-116 colon cancer cells and identification of curcuminoids as JMJD2 inhibitors.","date":"2014","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/24936217","citation_count":60,"is_preprint":false},{"pmid":"29077881","id":"PMC_29077881","title":"Interplay among H3K9-editing enzymes SUV39H1, JMJD2C and SRC-1 drives p66Shc transcription and vascular oxidative stress in obesity.","date":"2019","source":"European heart journal","url":"https://pubmed.ncbi.nlm.nih.gov/29077881","citation_count":59,"is_preprint":false},{"pmid":"31665047","id":"PMC_31665047","title":"JMJD2C promotes colorectal cancer metastasis via regulating histone methylation of MALAT1 promoter and enhancing β-catenin signaling pathway.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/31665047","citation_count":59,"is_preprint":false},{"pmid":"35121645","id":"PMC_35121645","title":"Targeting KDM4C enhances CD8+ T cell mediated antitumor immunity by activating chemokine CXCL10 transcription in lung cancer.","date":"2022","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35121645","citation_count":54,"is_preprint":false},{"pmid":"33462212","id":"PMC_33462212","title":"Histone demethylase KDM4C controls tumorigenesis of glioblastoma by epigenetically regulating p53 and c-Myc.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33462212","citation_count":51,"is_preprint":false},{"pmid":"34265399","id":"PMC_34265399","title":"UHRF1 promotes androgen receptor-regulated CDC6 transcription and anti-androgen receptor drug resistance in prostate cancer through KDM4C-Mediated chromatin modifications.","date":"2021","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/34265399","citation_count":49,"is_preprint":false},{"pmid":"31704649","id":"PMC_31704649","title":"KDM3A and KDM4C Regulate Mesenchymal Stromal Cell Senescence and Bone Aging via Condensin-mediated Heterochromatin Reorganization.","date":"2019","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/31704649","citation_count":46,"is_preprint":false},{"pmid":"19732750","id":"PMC_19732750","title":"Jmjd2c histone demethylase enhances the expression of Mdm2 oncogene.","date":"2009","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19732750","citation_count":46,"is_preprint":false},{"pmid":"26120059","id":"PMC_26120059","title":"Histone Demethylases KDM4A and KDM4C Regulate Differentiation of Embryonic Stem Cells to Endothelial Cells.","date":"2015","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26120059","citation_count":45,"is_preprint":false},{"pmid":"23698634","id":"PMC_23698634","title":"Histone demethylase KDM4C regulates sphere formation by mediating the cross talk between Wnt and Notch pathways in colonic cancer cells.","date":"2013","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/23698634","citation_count":43,"is_preprint":false},{"pmid":"29718303","id":"PMC_29718303","title":"The KDM4A/KDM4C/NF-κB and WDR5 epigenetic cascade regulates the activation of B cells.","date":"2018","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/29718303","citation_count":37,"is_preprint":false},{"pmid":"24728997","id":"PMC_24728997","title":"KDM4C (GASC1) lysine demethylase is associated with mitotic chromatin and regulates chromosome segregation during mitosis.","date":"2014","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/24728997","citation_count":36,"is_preprint":false},{"pmid":"11346465","id":"PMC_11346465","title":"A novel amplicon at 9p23 - 24 in squamous cell carcinoma of the esophagus that lies proximal to GASC1 and harbors NFIB.","date":"2001","source":"Japanese journal of cancer research : Gann","url":"https://pubmed.ncbi.nlm.nih.gov/11346465","citation_count":36,"is_preprint":false},{"pmid":"17611647","id":"PMC_17611647","title":"Comparative integromics on JMJD2A, JMJD2B and JMJD2C: preferential expression of JMJD2C in undifferentiated ES cells.","date":"2007","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17611647","citation_count":34,"is_preprint":false},{"pmid":"26149774","id":"PMC_26149774","title":"Jmjd2C increases MyoD transcriptional activity through inhibiting G9a-dependent MyoD degradation.","date":"2015","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/26149774","citation_count":33,"is_preprint":false},{"pmid":"31766290","id":"PMC_31766290","title":"Histone Demethylase KDM4C Stimulates the Proliferation of Prostate Cancer Cells via Activation of AKT and c-Myc.","date":"2019","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/31766290","citation_count":33,"is_preprint":false},{"pmid":"20410850","id":"PMC_20410850","title":"Analysis of 9p24 and 11p12-13 regions in autism spectrum disorders: rs1340513 in the JMJD2C gene is associated with ASDs in Finnish sample.","date":"2010","source":"Psychiatric genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20410850","citation_count":32,"is_preprint":false},{"pmid":"22072270","id":"PMC_22072270","title":"Genome-wide association study identifies 5q21 and 9p24.1 (KDM4C) loci associated with alcohol withdrawal symptoms.","date":"2011","source":"Journal of neural transmission (Vienna, Austria : 1996)","url":"https://pubmed.ncbi.nlm.nih.gov/22072270","citation_count":32,"is_preprint":false},{"pmid":"26747609","id":"PMC_26747609","title":"Opposing Chromatin Signals Direct and Regulate the Activity of Lysine Demethylase 4C (KDM4C).","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26747609","citation_count":30,"is_preprint":false},{"pmid":"32972441","id":"PMC_32972441","title":"microRNA-216b enhances cisplatin-induced apoptosis in osteosarcoma MG63 and SaOS-2 cells by binding to JMJD2C and regulating the HIF1α/HES1 signaling axis.","date":"2020","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/32972441","citation_count":29,"is_preprint":false},{"pmid":"21637537","id":"PMC_21637537","title":"Regulation of adipogenesis by nuclear receptor PPARγ is modulated by the histone demethylase JMJD2C.","date":"2011","source":"Genetics and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21637537","citation_count":29,"is_preprint":false},{"pmid":"38493716","id":"PMC_38493716","title":"Kaempferol inhibits colorectal cancer metastasis through circ_0000345 mediated JMJD2C/β-catenin signalling pathway.","date":"2024","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38493716","citation_count":28,"is_preprint":false},{"pmid":"21859682","id":"PMC_21859682","title":"High-throughput TR-FRET assays for identifying inhibitors of LSD1 and JMJD2C histone lysine demethylases.","date":"2011","source":"Journal of biomolecular screening","url":"https://pubmed.ncbi.nlm.nih.gov/21859682","citation_count":27,"is_preprint":false},{"pmid":"26722485","id":"PMC_26722485","title":"KDM4A, KDM4B and KDM4C in non-small cell lung cancer.","date":"2015","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26722485","citation_count":26,"is_preprint":false},{"pmid":"36804120","id":"PMC_36804120","title":"Luteolin directly binds to KDM4C and attenuates ovarian cancer stemness via epigenetic suppression of PPP2CA/YAP axis.","date":"2023","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/36804120","citation_count":25,"is_preprint":false},{"pmid":"18068534","id":"PMC_18068534","title":"Polycythemia vera transforming to acute myeloid leukemia and complex abnormalities including 9p homogeneously staining region with amplification of MLLT3, JMJD2C, JAK2, and SMARCA2.","date":"2008","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/18068534","citation_count":25,"is_preprint":false},{"pmid":"25014588","id":"PMC_25014588","title":"Substrate- and cofactor-independent inhibition of histone demethylase KDM4C.","date":"2014","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/25014588","citation_count":24,"is_preprint":false},{"pmid":"29374629","id":"PMC_29374629","title":"Cross-phenotype analysis of Immunochip data identifies KDM4C as a relevant locus for the development of systemic vasculitis.","date":"2018","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/29374629","citation_count":24,"is_preprint":false},{"pmid":"27840577","id":"PMC_27840577","title":"KDM4C Activity Modulates Cell Proliferation and Chromosome Segregation in Triple-Negative Breast Cancer.","date":"2016","source":"Breast cancer : basic and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/27840577","citation_count":23,"is_preprint":false},{"pmid":"28087629","id":"PMC_28087629","title":"Jmjd2c facilitates the assembly of essential enhancer-protein complexes at the onset of embryonic stem cell differentiation.","date":"2017","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/28087629","citation_count":22,"is_preprint":false},{"pmid":"37161649","id":"PMC_37161649","title":"BACH1 encourages ferroptosis by activating KDM4C-mediated COX2 demethylation after cerebral ischemia-reperfusion injury.","date":"2023","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/37161649","citation_count":22,"is_preprint":false},{"pmid":"37848946","id":"PMC_37848946","title":"KDM4C-mediated senescence defense is a targetable vulnerability in gastric cancer harboring TP53 mutations.","date":"2023","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/37848946","citation_count":22,"is_preprint":false},{"pmid":"27742014","id":"PMC_27742014","title":"KDM4C, a H3K9me3 Histone Demethylase, is Involved in the Maintenance of Human ESCC-Initiating Cells by Epigenetically Enhancing SOX2 Expression.","date":"2016","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/27742014","citation_count":21,"is_preprint":false},{"pmid":"25636512","id":"PMC_25636512","title":"Histone demethylase JMJD2B and JMJD2C induce fibroblast growth factor 2: mediated tumorigenesis of osteosarcoma.","date":"2015","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25636512","citation_count":17,"is_preprint":false},{"pmid":"35046387","id":"PMC_35046387","title":"JMJD2C-mediated long non-coding RNA MALAT1/microRNA-503-5p/SEPT2 axis worsens non-small cell lung cancer.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35046387","citation_count":16,"is_preprint":false},{"pmid":"34394903","id":"PMC_34394903","title":"KDM4C contributes to cytarabine resistance in acute myeloid leukemia via regulating the miR-328-3p/CCND2 axis through MALAT1.","date":"2021","source":"Therapeutic advances in chronic disease","url":"https://pubmed.ncbi.nlm.nih.gov/34394903","citation_count":16,"is_preprint":false},{"pmid":"21575637","id":"PMC_21575637","title":"Enzyme kinetic studies of histone demethylases KDM4C and KDM6A: towards understanding selectivity of inhibitors targeting oncogenic histone demethylases.","date":"2011","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/21575637","citation_count":16,"is_preprint":false},{"pmid":"33279929","id":"PMC_33279929","title":"Rare genetic variants in the gene encoding histone lysine demethylase 4C (KDM4C) and their contributions to susceptibility to schizophrenia and autism spectrum disorder.","date":"2020","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/33279929","citation_count":15,"is_preprint":false},{"pmid":"36012577","id":"PMC_36012577","title":"Essential Roles of the Histone Demethylase KDM4C in Renal Development and Acute Kidney Injury.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36012577","citation_count":15,"is_preprint":false},{"pmid":"33692332","id":"PMC_33692332","title":"GASC1 promotes hepatocellular carcinoma progression by inhibiting the degradation of ROCK2.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33692332","citation_count":14,"is_preprint":false},{"pmid":"37117173","id":"PMC_37117173","title":"KDM4C silencing inhibits cell migration and enhances radiosensitivity by inducing CXCL2 transcription in hepatocellular carcinoma.","date":"2023","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/37117173","citation_count":12,"is_preprint":false},{"pmid":"29207681","id":"PMC_29207681","title":"Histone demethylase JMJD2C: epigenetic regulators in tumors.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29207681","citation_count":11,"is_preprint":false},{"pmid":"33649841","id":"PMC_33649841","title":"GASC1 promotes glioma progression by enhancing NOTCH1 signaling.","date":"2021","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/33649841","citation_count":11,"is_preprint":false},{"pmid":"31031809","id":"PMC_31031809","title":"GASC1 Promotes Stemness of Esophageal Squamous Cell Carcinoma via NOTCH1 Promoter Demethylation.","date":"2019","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31031809","citation_count":11,"is_preprint":false},{"pmid":"31784197","id":"PMC_31784197","title":"Rational design, synthesis and biological profiling of new KDM4C inhibitors.","date":"2019","source":"Bioorganic & medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31784197","citation_count":11,"is_preprint":false},{"pmid":"38877874","id":"PMC_38877874","title":"Synergistic effects of the KDM4C inhibitor SD70 and the menin inhibitor MI-503 against MLL::AF9-driven acute myeloid leukaemia.","date":"2024","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/38877874","citation_count":10,"is_preprint":false},{"pmid":"35654819","id":"PMC_35654819","title":"Histone demethylase KDM4C is a functional dependency in JAK2-mutated neoplasms.","date":"2022","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/35654819","citation_count":10,"is_preprint":false},{"pmid":"26248577","id":"PMC_26248577","title":"The oncogenic role of GASC1 in chemically induced mouse skin cancer.","date":"2015","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/26248577","citation_count":10,"is_preprint":false},{"pmid":"32195022","id":"PMC_32195022","title":"Histone demethylase KDM4C activates HIF1α/VEGFA signaling through the costimulatory factor STAT3 in NSCLC.","date":"2020","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/32195022","citation_count":10,"is_preprint":false},{"pmid":"35468881","id":"PMC_35468881","title":"JMJD2C mediates the MDM2/p53/IL5RA axis to promote CDDP resistance in uveal melanoma.","date":"2022","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/35468881","citation_count":8,"is_preprint":false},{"pmid":"33469678","id":"PMC_33469678","title":"JMJD2C triggers the growth of multiple myeloma cells via activation of β‑catenin.","date":"2021","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/33469678","citation_count":8,"is_preprint":false},{"pmid":"32908544","id":"PMC_32908544","title":"Histone Demethylase KDM4C Is Required for Ovarian Cancer Stem Cell Maintenance.","date":"2020","source":"Stem cells international","url":"https://pubmed.ncbi.nlm.nih.gov/32908544","citation_count":8,"is_preprint":false},{"pmid":"38421303","id":"PMC_38421303","title":"KDM4C promotes mouse hippocampal neural stem cell proliferation through modulating ApoE expression.","date":"2024","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/38421303","citation_count":7,"is_preprint":false},{"pmid":"39807336","id":"PMC_39807336","title":"Avenanthramide A potentiates Bim-mediated antineoplastic properties of 5-fluorouracil via targeting KDM4C/MIR17HG/GSK-3β negative feedback loop in colorectal cancer.","date":"2024","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/39807336","citation_count":7,"is_preprint":false},{"pmid":"36709354","id":"PMC_36709354","title":"The histone demethylase JMJD2C constitutes a novel NFE2 target gene that is required for the survival of JAK2V617F mutated cells.","date":"2023","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/36709354","citation_count":7,"is_preprint":false},{"pmid":"32411232","id":"PMC_32411232","title":"GASC1-Adapted Neoadjuvant Chemotherapy for Resectable Esophageal Squamous Cell Carcinoma: A Prospective Clinical Biomarker Trial.","date":"2020","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32411232","citation_count":7,"is_preprint":false},{"pmid":"38252669","id":"PMC_38252669","title":"The promotive role of lncRNA MIR205HG in proliferation, invasion, and migration of melanoma cells via the JMJD2C/ALKBH5 axis.","date":"2024","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/38252669","citation_count":7,"is_preprint":false},{"pmid":"34121556","id":"PMC_34121556","title":"MicroRNA-340-5p inhibits endothelial apoptosis, inflammatory response, and pro-coagulation by targeting KDM4C in anti-neutrophil cytoplasmic antibody (ANCA)-mediated glomerulonephritis through activation of B cells.","date":"2021","source":"Autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/34121556","citation_count":7,"is_preprint":false},{"pmid":"40457074","id":"PMC_40457074","title":"KDM4C inhibition blocks tumor growth in basal breast cancer by promoting cathepsin L-mediated histone H3 cleavage.","date":"2025","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40457074","citation_count":6,"is_preprint":false},{"pmid":"35522148","id":"PMC_35522148","title":"Focal structural variants revealed by whole genome sequencing disrupt the histone demethylase KDM4C in B-cell lymphomas.","date":"2023","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/35522148","citation_count":6,"is_preprint":false},{"pmid":"28396876","id":"PMC_28396876","title":"Reduced Histone H3 Lysine 9 Methylation Contributes to the Pathogenesis of Latent Autoimmune Diabetes in Adults via Regulation of SUV39H2 and KDM4C.","date":"2017","source":"Journal of diabetes research","url":"https://pubmed.ncbi.nlm.nih.gov/28396876","citation_count":6,"is_preprint":false},{"pmid":"27223606","id":"PMC_27223606","title":"Post-Transcriptional Regulation of the GASC1 Oncogene with Active Tumor-Targeted siRNA-Nanoparticles.","date":"2016","source":"Molecular pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/27223606","citation_count":5,"is_preprint":false},{"pmid":"38938016","id":"PMC_38938016","title":"KDM4C represses liver fibrosis by regulating H3K9me3 methylation of ALKBH5 and m6A methylation of snail1 mRNA.","date":"2024","source":"Journal of digestive diseases","url":"https://pubmed.ncbi.nlm.nih.gov/38938016","citation_count":5,"is_preprint":false},{"pmid":"34281993","id":"PMC_34281993","title":"Novel germline variant in the histone demethylase and transcription regulator KDM4C induces a multi-cancer phenotype.","date":"2021","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34281993","citation_count":5,"is_preprint":false},{"pmid":"30083054","id":"PMC_30083054","title":"Kdm4c is Recruited to Mitotic Chromosomes and Is Relevant for Chromosomal Stability, Cell Migration and Invasion of Triple Negative Breast Cancer Cells.","date":"2018","source":"Breast cancer : basic and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/30083054","citation_count":5,"is_preprint":false},{"pmid":"39726315","id":"PMC_39726315","title":"KDM4C and GFPT1: Potential Therapeutic Targets for Gastric Cancer.","date":"2024","source":"Discovery medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39726315","citation_count":4,"is_preprint":false},{"pmid":"38623585","id":"PMC_38623585","title":"Identification of KDM4C as a gene conferring drug resistance in multiple myeloma.","date":"2024","source":"Open life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38623585","citation_count":4,"is_preprint":false},{"pmid":"35886932","id":"PMC_35886932","title":"KDM4C Contributes to Trophoblast-like Stem Cell Conversion from Porcine-Induced Pluripotent Stem Cells (piPSCs) via Regulating CDX2.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35886932","citation_count":4,"is_preprint":false},{"pmid":"35414503","id":"PMC_35414503","title":"Histone Demethylase GASC1 Inhibitor Targeted GASC1 Gene to Inhibit the Malignant Transformation of Esophageal Cancer through the NOTCH-MAPK Signaling Pathway.","date":"2022","source":"Annals of clinical and laboratory science","url":"https://pubmed.ncbi.nlm.nih.gov/35414503","citation_count":3,"is_preprint":false},{"pmid":"40259045","id":"PMC_40259045","title":"KDM4C works in concert with GATA1 to regulate heme metabolism in head and neck squamous cell carcinoma.","date":"2025","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/40259045","citation_count":2,"is_preprint":false},{"pmid":"40280301","id":"PMC_40280301","title":"Targeted inhibition of JMJD2C/MALAT1 axis compensates for the deficiency of metformin in reversing ovarian cancer platinum resistance.","date":"2025","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40280301","citation_count":2,"is_preprint":false},{"pmid":"38975736","id":"PMC_38975736","title":"Jmjd2c maintains the ALDHbri+ cancer stemness with transcription factor SOX2 in lung squamous cell carcinoma.","date":"2024","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/38975736","citation_count":2,"is_preprint":false},{"pmid":"40424935","id":"PMC_40424935","title":"USP35 promotes hepatocellular carcinoma proliferation through GASC1-mediated ROCK2 upregulation.","date":"2025","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40424935","citation_count":2,"is_preprint":false},{"pmid":"40716534","id":"PMC_40716534","title":"KDM4C regulates trophoblast proliferation and migration in preeclampsia via the NFATc4/Wnt pathway.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40716534","citation_count":1,"is_preprint":false},{"pmid":"40975760","id":"PMC_40975760","title":"Fumarate activates the IL-6/JAK/STAT3 pathway by inhibiting KDM4C-mediated H3K36me3 demethylation in FH-knockdown renal cancer cells.","date":"2025","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40975760","citation_count":1,"is_preprint":false},{"pmid":"41490602","id":"PMC_41490602","title":"The Lysine Demethylase KDM4C Is an Oncogenic Driver and Regulates ERK Activity in KRAS-Mutant Pancreatic Ductal Adenocarcinoma.","date":"2026","source":"Cancer research communications","url":"https://pubmed.ncbi.nlm.nih.gov/41490602","citation_count":1,"is_preprint":false},{"pmid":"41217736","id":"PMC_41217736","title":"Histone demethylase KDM4C confers temozolomide resistance to glioblastoma cells by epigenetically regulating E2F6.","date":"2025","source":"Archives of pharmacal research","url":"https://pubmed.ncbi.nlm.nih.gov/41217736","citation_count":1,"is_preprint":false},{"pmid":"41505486","id":"PMC_41505486","title":"Targeting epigenetic regulators: In-silico discovery of natural inhibitors against histone demethylase KDM4C.","date":"2026","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/41505486","citation_count":1,"is_preprint":false},{"pmid":"40711862","id":"PMC_40711862","title":"Impact of KDM4C on the radiosensitivity of glioblastoma cells.","date":"2025","source":"International journal of radiation biology","url":"https://pubmed.ncbi.nlm.nih.gov/40711862","citation_count":0,"is_preprint":false},{"pmid":"40635012","id":"PMC_40635012","title":"Mutation of the histone demethylase Gasc1 causes ASD-like symptoms in mice.","date":"2025","source":"Inflammation and regeneration","url":"https://pubmed.ncbi.nlm.nih.gov/40635012","citation_count":0,"is_preprint":false},{"pmid":"41680357","id":"PMC_41680357","title":"Rare KDM4C variants and reduced expression underlie epigenetic dysregulation in rheumatoid arthritis.","date":"2026","source":"Immunologic research","url":"https://pubmed.ncbi.nlm.nih.gov/41680357","citation_count":0,"is_preprint":false},{"pmid":"40778546","id":"PMC_40778546","title":"Luteolin Alleviates Diabetic Foot Ulcers Through Improving KDM4C/ITGA1-mediated Functional Impairments of AGEs-Induced Senescent Endothelial Cell.","date":"2025","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/40778546","citation_count":0,"is_preprint":false},{"pmid":"39900886","id":"PMC_39900886","title":"Targeting KDM4C Prevents Heart Failure after Acute Myocardial Infarction Via Activation of SOS2.","date":"2025","source":"Journal of cardiovascular translational research","url":"https://pubmed.ncbi.nlm.nih.gov/39900886","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.31.635709","title":"Heterochromatin fidelity is a therapeutic vulnerability in lymphoma and other human cancers","date":"2025-02-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.31.635709","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.28.25324850","title":"Whole-Genome Sequencing Reveals Individual and Cohort Level Insights into Chromosome 9p Syndromes","date":"2025-03-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.28.25324850","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53474,"output_tokens":10334,"usd":0.157716,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20734,"output_tokens":5169,"usd":0.116447,"stage2_stop_reason":"end_turn"},"total_usd":0.274163,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"GASC1/JMJD2C (KDM4C) demethylates tri- and dimethylated lysine 9 on histone H3 (H3K9me3/me2) via a hydroxylation reaction requiring iron and alpha-ketoglutarate as cofactors. Ectopic expression decreases H3K9me3/me2 levels, increases H3K9me1, delocalizes HP1, and reduces heterochromatin in vivo.\",\n      \"method\": \"In vitro demethylase assay with iron/alpha-KG cofactors; ectopic expression in cells with chromatin analysis; HP1 delocalization assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic reconstitution with cofactor requirements established, validated in vivo by multiple orthogonal methods, highly cited foundational study\",\n      \"pmids\": [\"16732293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Jmjd2c is positively regulated by Oct4 in embryonic stem cells. Jmjd2c depletion causes ES cell differentiation and reduces Nanog expression. Jmjd2c demethylates H3K9me3 at the Nanog promoter, preventing binding of transcriptional repressors HP1 and KAP1.\",\n      \"method\": \"RNAi knockdown; ChIP assay at Nanog promoter; gene expression analysis; ES cell differentiation assay\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal ChIP, RNAi loss-of-function with defined cellular phenotype, replicated in subsequent studies\",\n      \"pmids\": [\"17938240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Jmjd2c is recruited to the P2 promoter region of the Mdm2 oncogene, demethylates H3K9 there, and increases Mdm2 expression in a demethylase-activity-dependent manner, leading to reduction of p53 protein levels.\",\n      \"method\": \"ChIP assay; overexpression and siRNA knockdown; Western blot for p53 and Mdm2\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus loss/gain-of-function, single lab, two orthogonal methods\",\n      \"pmids\": [\"19732750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"JMJD2C selectively interacts with HIF-1α (but not HIF-2α) and is recruited by HIF-1α to hypoxia response elements of target genes. JMJD2C decreases H3K9me3 at these elements, enhancing HIF-1 binding and activating transcription of BNIP3, LDHA, PDK1, SLC2A1, LOXL2, and L1CAM. JMJD2C knockdown inhibits breast tumor growth and lung metastasis in mice.\",\n      \"method\": \"Co-immunoprecipitation; ChIP; knockdown with xenograft tumor model; gene expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP, in vivo xenograft with defined molecular mechanism, multiple orthogonal methods\",\n      \"pmids\": [\"23129632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Jmjd2c depletion in mouse ESCs impairs differentiation and leads to a post-implantation epiblast-like arrest. Jmjd2c is re-distributed to lineage-specific enhancers during ESC priming. Loss of Jmjd2c abrogates G9a recruitment and destabilizes loading of mediator (Med1) and cohesin (Smc1a) at newly activated/poised enhancers, implicating Jmjd2c as a molecular scaffold for enhancer-protein complex assembly.\",\n      \"method\": \"Jmjd2c knockout ESCs; ChIP-seq; co-occupancy analysis; differentiation assays\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout ESC model, genome-wide ChIP-seq, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"28087629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KDM4C binds to the β-catenin target gene JAG1 promoter and is required for β-catenin recruitment to JAG1 independently of H3K9 methylation status; this feed-forward mechanism drives colonosphere formation in colorectal cancer cells.\",\n      \"method\": \"ChIP; siRNA knockdown; colonosphere formation assay; microarray gene expression\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional knockdown, single lab, two orthogonal methods\",\n      \"pmids\": [\"23698634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Jmjd2c and Jmjd2b have distinct genomic targets in ESCs: Jmjd2c uniquely targets Polycomb repressive complex (PRC) module sites and assists PRC2 in transcriptional repression, while Jmjd2b operates through the Core module. Both are required for induced pluripotent stem cell generation.\",\n      \"method\": \"RNAi screen; genome-wide ChIP-seq occupancy; iPSC reprogramming assay; double knockdown\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq, functional RNAi screen, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"24361252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"JMJD2C localizes to H3K4me3-positive transcription start sites via its double Tudor domain (TTD), which recognizes H3K4me3 but not H4K20me2/me3 in vitro—a binding specificity different from JMJD2A and JMJD2B Tudor domains. Depletion in KYSE150 carcinoma cells impairs proliferation and deregulates target genes involved in cell cycle progression, with modest effects on global H3K9me3 and H3K36me3.\",\n      \"method\": \"Jmjd2c knockout mice; ChIP-seq; in vitro Tudor domain binding assay; siRNA knockdown in carcinoma cells\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro domain binding assay, genome-wide ChIP-seq, knockout mouse, multiple orthogonal methods\",\n      \"pmids\": [\"24396064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KDM4C is associated with mitotic chromatin, mediated by its C-terminal Tudor domains; the R919 residue on the proximal Tudor domain is critical for this mitotic chromatin association. Depletion or overexpression of KDM4C causes >3-fold increase in abnormal mitosis including misaligned chromosomes and anaphase bridges. A demethylase-dead mutant has no effect on chromosome segregation, implicating catalytic activity in mitotic fidelity.\",\n      \"method\": \"Live-cell imaging; immunofluorescence; point mutant overexpression; siRNA knockdown; mitotic error scoring\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiment, domain/point-mutant functional dissection, catalytic dead mutant control, defined mitotic phenotype\",\n      \"pmids\": [\"24728997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KDM4C forms a complex with β-catenin in colon cancer cells (co-immunoprecipitation). KDM4C downregulation reduces growth, clonogenicity, and expression of FRA1, cyclin D1, and BCL2 in HCT-116 cells.\",\n      \"method\": \"Co-immunoprecipitation; siRNA knockdown; proliferation and clonogenic assays; Western blot\",\n      \"journal\": \"American Journal of Translational Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP plus functional knockdown, single lab\",\n      \"pmids\": [\"24936217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IP6K1-synthesized inositol pyrophosphate (IP7) interacts with JMJD2C and causes its dissociation from chromatin, increasing H3K9me3 levels; reduced IP7 (via IP6K1 RNAi or ip6k1-/- MEFs) leads to decreased H3K9me3 and increased H3K9ac, with downstream changes in JMJD2C target gene transcription.\",\n      \"method\": \"Co-immunoprecipitation; IP6K1 RNAi and knockout MEFs; chromatin fractionation; histone modification analysis; gene expression assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, genetic knockout model, two orthogonal methods, single lab\",\n      \"pmids\": [\"24191012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The Tudor domain (TTD) of KDM4C recognizes H3K4me3 and this recognition stimulates KDM4C-mediated demethylation of H3K9me3 in cis on peptide and mononucleosome substrates, establishing a multivalent interaction mechanism that facilitates mutual exclusion of H3K4me3 and H3K9me3 marks.\",\n      \"method\": \"In vitro demethylase assay with peptide and mononucleosome substrates; quantitative TTD binding assays; kinetic analysis\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution on defined substrates, kinetic quantification, mechanistic mutagenesis-adjacent domain analysis\",\n      \"pmids\": [\"26747609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KDM4C transcriptionally activates serine-glycine biosynthesis and amino acid transport genes by removing H3K9me3 from their promoters. This activity requires ATF4: KDM4C activates ATF4 transcription and physically interacts with ATF4 to co-target serine pathway genes, leading to increased intracellular amino acid levels.\",\n      \"method\": \"ChIP; co-immunoprecipitation; metabolomics; siRNA knockdown; gene expression analysis\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, Co-IP, metabolomics, and functional knockdown, multiple orthogonal methods in single study\",\n      \"pmids\": [\"26774480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Jmjd2c directly associates with MyoD in vitro and in vivo, demethylates MyoD, and stabilizes MyoD by inhibiting G9a-dependent methylation-driven MyoD ubiquitination (through the Cul4/Ddb1/Dcaf1 pathway). Stabilized MyoD activates myogenic target genes; Jmjd2c also erases H3K9me3 at MyoD target gene promoters.\",\n      \"method\": \"GST pull-down; co-immunoprecipitation; in vitro demethylation assay; ubiquitination assay; myogenic conversion assay; ChIP\",\n      \"journal\": \"Biochimica et Biophysica Acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro pull-down plus Co-IP, enzymatic demethylation of non-histone substrate, ubiquitination mechanistic dissection, multiple orthogonal methods\",\n      \"pmids\": [\"26149774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KDM4C binds to histones at the VE-cadherin promoter and is required for VE-cadherin expression and mouse ESC differentiation to endothelial cells; KDM4C depletion impairs capillary tube formation and vasculogenesis.\",\n      \"method\": \"ChIP; siRNA knockdown; endothelial differentiation assay; tube formation assay; zebrafish vasculogenesis model\",\n      \"journal\": \"Stem Cell Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional knockdown, in vivo zebrafish model, single lab\",\n      \"pmids\": [\"26120059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"JMJD2C reduces H3K9me3 and H3K36me3 at the MALAT1 promoter, upregulating MALAT1 expression, which activates the β-catenin signaling pathway and promotes colorectal cancer metastasis. JMJD2C protein translocates to the nucleus to execute this function.\",\n      \"method\": \"ChIP-PCR; luciferase reporter assay; siRNA knockdown/overexpression; Western blot; in vivo metastasis model\",\n      \"journal\": \"Journal of Experimental & Clinical Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, luciferase reporter, functional assays, single lab\",\n      \"pmids\": [\"31665047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SUV39H1, JMJD2C, and SRC-1 form an interacting regulatory axis at the p66Shc promoter: SUV39H1 is the upstream effector orchestrating JMJD2C/SRC-1 recruitment. JMJD2C demethylates H3K9 at the p66Shc promoter, contributing to p66Shc transcription and ROS-driven endothelial dysfunction in obesity.\",\n      \"method\": \"ChIP; siRNA reprogramming in isolated endothelial cells and aortas; genetic manipulation in obese mice; ROS/NO measurement\",\n      \"journal\": \"European Heart Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, in vivo genetic models, mechanistic epistasis established, single lab\",\n      \"pmids\": [\"29077881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM4C regulates ALKBH5 (m6A demethylase) expression by reducing H3K9me3 levels and increasing chromatin accessibility at the ALKBH5 locus, thereby promoting recruitment of MYB and Pol II. In AML, this axis drives leukemia stem cell maintenance via ALKBH5-dependent stabilization of AXL mRNA.\",\n      \"method\": \"ChIP; ATAC-seq; siRNA/shRNA knockdown; xenograft leukemia stem cell assays; RNA m6A analysis\",\n      \"journal\": \"Cell Stem Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, ATAC-seq, in vivo LSC functional assays, multiple orthogonal methods, rigorous controls\",\n      \"pmids\": [\"32402251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP9X deubiquitinates and stabilizes KDM4C protein. KDM4C upregulates TGF-β2 expression by directly reducing H3K9me3 at the TGF-β2 promoter, activating Smad/ATM/Chk2 signaling and conferring radioresistance in lung cancer. Depletion of USP9X destabilizes KDM4C and impairs TGF-β2/Smad signaling.\",\n      \"method\": \"Tandem affinity purification; co-immunoprecipitation; ChIP; ubiquitination assay; siRNA knockdown; xenograft model\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — TAP identification of binding partner, Co-IP, ChIP, in vivo xenograft, multiple orthogonal methods\",\n      \"pmids\": [\"33558705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM4C suppresses the pro-apoptotic functions of p53 by demethylating p53 at K372me1, which is pivotal for the stability of chromatin-bound p53. KDM4C also binds to the c-Myc promoter and induces c-Myc expression. A catalytic dead KDM4C mutant fails to rescue proliferation after knockdown.\",\n      \"method\": \"Catalytic dead mutant rescue experiment; ChIP; Western blot; apoptosis assay; in vitro and in vivo glioblastoma models\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic dead mutant used, ChIP for c-Myc promoter, single lab, multiple methods\",\n      \"pmids\": [\"33462212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UHRF1 recruits KDM4C to the CDC6 promoter, where KDM4C demethylates H3K9me2/3 to convert heterochromatin to a permissive state, enabling androgen receptor occupancy and CDC6 transcription, contributing to anti-androgen resistance in prostate cancer.\",\n      \"method\": \"ChIP; co-immunoprecipitation; siRNA knockdown; xenograft model\",\n      \"journal\": \"Cancer Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus Co-IP, functional knockdown, single lab\",\n      \"pmids\": [\"34265399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM3A and KDM4C transcriptionally activate condensin components NCAPD2 and NCAPG2 via H3K9 demethylation, leading to heterochromatin reorganization during MSC senescence. Suppression of KDM4C aggravates DNA damage response and cellular senescence; overexpression promotes heterochromatin reorganization and blunts DNA damage.\",\n      \"method\": \"siRNA/shRNA knockdown; overexpression; ChIP; DNA damage assays; Kdm3a-/- mouse model\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, genetic knockout mouse, functional assays, single lab\",\n      \"pmids\": [\"31704649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KDM4C inhibition increases H3K36me3 binding at the CXCL10 promoter, inducing CXCL10 transcription and enhancing CD8+ T cell-mediated antitumor immunity in lung cancer. Genetic or pharmacological KDM4C inhibition specifically increased CD8+ T cell infiltration and activation.\",\n      \"method\": \"ChIP-PCR; RNA-seq; flow cytometry; in vivo mouse tumor model; pharmacological inhibitor SD70\",\n      \"journal\": \"Journal for Immunotherapy of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, RNA-seq, in vivo model, single lab, multiple methods\",\n      \"pmids\": [\"35121645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KDM4A and KDM4C interact with NF-κB p65 and co-target the Wdr5 locus (a MLL complex member promoting H3K4 methylation), upregulating cell cycle inhibitors Cdkn2c and Cdkn3 in activated B cells. ChIP-seq revealed NF-κB p65 as a binding partner.\",\n      \"method\": \"ChIP-seq; de novo motif analysis; co-immunoprecipitation; siRNA knockdown; B cell proliferation assay\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, Co-IP, functional knockdown, single lab\",\n      \"pmids\": [\"29718303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Substrate- and cofactor-independent cyclic peptide inhibitors of KDM4C were identified by phage display screening. Hydrogen/deuterium exchange mass spectrometry showed these peptides interact with KDM4C at surface regions remote from the active site, providing a new mode of inhibition.\",\n      \"method\": \"Phage display screening; H/D exchange mass spectrometry; in vitro inhibition assays; peptide SAR\",\n      \"journal\": \"ACS Chemical Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical assays, HD-exchange MS structural characterization, single lab\",\n      \"pmids\": [\"25014588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GASC1/KDM4C transcriptionally represses FBXO42 (a ROCK2 ubiquitin ligase) via its demethylase activity, thereby preventing K63-linked poly-ubiquitination and degradation of ROCK2, promoting hepatocellular carcinoma growth.\",\n      \"method\": \"siRNA knockdown; ubiquitination assay; ChIP; demethylase inhibitor treatment; xenograft model\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, ubiquitination assay, functional knockdown, single lab\",\n      \"pmids\": [\"33692332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BACH1 binds to the KDM4C promoter to transcriptionally activate KDM4C expression. KDM4C in turn occupies the COX2 gene promoter and promotes COX2 expression by eliminating H3K9me3, contributing to ferroptosis in neuroblastoma and cerebral ischemia-reperfusion injury.\",\n      \"method\": \"ChIP; siRNA knockdown; overexpression rescue; in vivo MCAO mouse model\",\n      \"journal\": \"The European Journal of Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, genetic manipulation, in vivo model, single lab\",\n      \"pmids\": [\"37161649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KDM4C loss in JAK2-mutated cells results in alterations of H3K9me3 target gene expression, loss of cell competition, reduced proliferation, and induction of cellular senescence, establishing KDM4C as a selective genetic dependency in JAK2-mutated myeloid neoplasms.\",\n      \"method\": \"Genetic inactivation (CRISPR); xenograft models; histone methylation analysis; gene expression; senescence assays\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR knockout, in vivo xenograft, multiple functional readouts, single lab\",\n      \"pmids\": [\"35654819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NFE2 directly activates JMJD2C transcription as a target gene. Loss of JMJD2C selectively impairs proliferation of JAK2V617F mutated cells, linking NFE2-driven leukemogenesis to KDM4C upregulation.\",\n      \"method\": \"Chromatin immunoprecipitation; shRNA knockdown; proliferation assays in JAK2V617F and transgenic mouse models\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating NFE2 binding, functional knockdown, single lab\",\n      \"pmids\": [\"36709354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In KDM4C-amplified basal breast cancer, KDM4C inhibition does not primarily alter H3K9me3/H3K36me3 but instead causes methylation of GRHL2 at K453, which recruits cathepsin L (CTSL) to chromatin. CTSL then cleaves histone H3, decreasing glutamate-cysteine ligase expression and increasing reactive oxygen species. CTSL deletion rescues KDM4C-loss-mediated tumor suppression.\",\n      \"method\": \"CRISPR KO; proteomics; chromatin fractionation; CTSL activity assays; rescue experiments; transcriptomic analysis\",\n      \"journal\": \"Nature Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods, genetic rescue, identifies non-canonical mechanism distinct from H3K9/36 demethylation, rigorous controls\",\n      \"pmids\": [\"40457074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"KDM4C interacts with SIRT1 via its Tudor reader domain (identified by proximity labeling). KDM4C loss reduces phospho-ERK in KRAS-mutant PDAC cells; mechanistically, KDM4C-SIRT1 interaction represses DUSP2 (an ERK-inactivating phosphatase), sustaining ERK signaling. CRISPR deletion of KDM4C reduces proliferation and improves survival in orthotopic PDAC models.\",\n      \"method\": \"Proximity labeling (BioID); CRISPR/Cas9 deletion; transcriptomic and proteomic analysis; in vivo orthotopic allograft model; phospho-ERK measurement\",\n      \"journal\": \"Cancer Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity labeling for interaction, CRISPR KO with in vivo validation, mechanistic pathway placement, single lab\",\n      \"pmids\": [\"41490602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"JMJD2C promotes esophageal squamous cell carcinoma stemness by demethylating H3K9me2/me3 at the NOTCH1 promoter, increasing NOTCH1 expression. Blockade of GASC1 increases NOTCH1 promoter H3K9me2/me3 and decreases NOTCH1 and ALDHbri+ cancer stem cell properties; NOTCH1 overexpression rescues these effects.\",\n      \"method\": \"ChIP; siRNA/shRNA knockdown; lentiviral overexpression rescue; ALDH+ cell sorting; in vivo xenograft\",\n      \"journal\": \"Journal of Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with rescue experiment, in vivo model, single lab\",\n      \"pmids\": [\"31031809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KDM4C demethylase activity is required for expression of FGF2 in osteosarcoma; GST pull-down showed JMJD2C interacts with FGF2 protein.\",\n      \"method\": \"GST pull-down; siRNA knockdown; Western blot; RT-PCR\",\n      \"journal\": \"Medical Oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single GST pull-down, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"25636512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM4C reduces H3K9me3 at the ALKBH5 promoter to upregulate ALKBH5 expression; ALKBH5 then demethylates snail1 mRNA m6A modification to reduce its stability, thereby inhibiting liver fibrosis. ChIP-qPCR confirmed KDM4C binding and H3K9me3 reduction at the ALKBH5 promoter.\",\n      \"method\": \"ChIP-qPCR; overexpression/knockdown; RNA m6A quantification; in vivo CCl4 fibrosis model; Western blot\",\n      \"journal\": \"Journal of Digestive Diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, m6A analysis, in vivo model, single lab\",\n      \"pmids\": [\"38938016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KDM4C interacts with GATA1 (confirmed by immunoprecipitation and docking) and co-regulates ferrochelatase (FECH) in heme metabolism in head and neck squamous cell carcinoma. FECH overexpression rescues cell migration and invasion suppressed by KDM4C or GATA1 knockdown.\",\n      \"method\": \"Co-immunoprecipitation; molecular docking; RNA-seq; CUT&Tag-seq; siRNA knockdown; zebrafish and mouse xenograft models\",\n      \"journal\": \"Cellular and Molecular Life Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, genome-wide CUT&Tag, rescue experiment, in vivo models, single lab\",\n      \"pmids\": [\"40259045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Jmjd2c and SOX2 proteins physically interact with each other (Co-IP and GST pull-down confirmed); Jmjd2c is required for SOX2 expression in ALDHbri+ lung squamous cancer stem cells, and Jmjd2c-SOX2 double silencing has enhanced tumor suppression relative to either alone.\",\n      \"method\": \"Co-immunoprecipitation; GST pull-down; shRNA knockdown; tumor xenograft model\",\n      \"journal\": \"Cancer Biology & Therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal Co-IP and pull-down confirming interaction, functional knockdown, single lab\",\n      \"pmids\": [\"38975736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KDM4C overexpression upregulates ApoE expression in mouse hippocampal neural stem cells, promoting their proliferation; ApoE knockdown mitigates this proliferative effect, placing ApoE downstream of KDM4C.\",\n      \"method\": \"Lentiviral overexpression; RNA-seq; BrdU/Ki-67 staining; ApoE siRNA knockdown\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lentiviral overexpression, RNA-seq, functional rescue by ApoE knockdown, single lab\",\n      \"pmids\": [\"38421303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In preeclampsia, KDM4C reduces H3K9me3 at the NFATc4 locus, increasing NFATc4 expression. NFATc4 then inhibits β-catenin nuclear translocation by binding Dishevelled (Dvl), disrupting Wnt/β-catenin signaling and suppressing trophoblast proliferation and migration.\",\n      \"method\": \"ChIP; siRNA overexpression/knockdown; co-immunoprecipitation; in vivo L-NAME-induced PE rat model; immunohistochemistry\",\n      \"journal\": \"International Journal of Biological Macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, Co-IP, in vivo model, mechanistic pathway placement, single lab\",\n      \"pmids\": [\"40716534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Fumarate accumulation in FH-deficient renal cancer cells competitively inhibits KDM4C activity (by competing with α-ketoglutarate), leading to elevated H3K36me3 at target loci, activation of IL-6/JAK/STAT3 signaling, and increased CXCL10 and PD-L1 expression. In vitro and in vivo experiments confirmed fumarate's inhibitory effect on KDM4C.\",\n      \"method\": \"In vitro KDM4C activity assay with fumarate; ChIP-qPCR; siRNA knockdown; in vivo FH-knockdown models; RNA-seq\",\n      \"journal\": \"British Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro enzyme inhibition assay, ChIP, in vivo models, single lab\",\n      \"pmids\": [\"40975760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KDM4C overexpression in glioblastoma cells reduces IR-induced DNA damage response and apoptosis; a catalytic inhibitor (SD70) reverses these effects. KDM4C overexpression causes broad transcriptional remodeling after irradiation, reducing radiosensitivity.\",\n      \"method\": \"KDM4C overexpression; clonogenic survival assay; DNA damage assay; apoptosis analysis; pharmacological inhibitor SD70; in vivo xenograft\",\n      \"journal\": \"International Journal of Radiation Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function plus pharmacological inhibition, in vivo xenograft, defined phenotype, single lab\",\n      \"pmids\": [\"40711862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AVN A (Avenanthramide A) directly binds to the S198 site of KDM4C, promoting its degradation, thereby increasing H3K9me3 occupancy at the MIR17HG promoter, blocking MIR17HG transcription and derepressing Bim expression in colorectal cancer.\",\n      \"method\": \"Molecular-protein docking; cellular thermal shift assay (CETSA); ChIP; dual luciferase reporter; CRC organoids; Apc mouse model\",\n      \"journal\": \"Acta Pharmaceutica Sinica B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CETSA for direct binding, ChIP for mechanistic effect, in vivo models, single lab\",\n      \"pmids\": [\"39807336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Structural variants in KDM4C result in loss-of-function in B-cell lymphomas. Functional reconstitution studies in lymphoma cell lines provided evidence that KDM4C can act as a tumor suppressor in this context.\",\n      \"method\": \"Whole genome sequencing; RNA-seq; functional reconstitution in cell lines; focal homozygous deletion identification\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reconstitution in cell lines, genomic and transcriptomic integration, single lab\",\n      \"pmids\": [\"35522148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Enzymatic characterization of KDM4C demonstrates selectivity for H3K9me3 substrate; inhibition studies with 2,4-dicarboxypyridine and (R)-N-oxalyl-O-benzyltyrosine showed significant selectivity between KDM4C and KDM6A despite similar active site topologies.\",\n      \"method\": \"In vitro enzyme kinetics; inhibitor selectivity assay\",\n      \"journal\": \"FEBS Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic characterization with kinetic measurements, single lab\",\n      \"pmids\": [\"21575637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KDM4C inhibition in DLBCL cells causes epigenomic rewiring of heterochromatin; KDM4 demethylases associate with KRAB zinc finger protein ZNF587, and their enzymatic inhibition leads to DNA replication stress and DNA damage-induced cGAS-STING activation.\",\n      \"method\": \"Phenotypic screen; biochemical interaction analysis; cGAS-STING activation assay; high-throughput small molecule screen with nucleosome substrates\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — preprint, biochemical interaction, phenotypic screen, not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"KDM4C (GASC1/JMJD2C) is a Jumonji-C domain histone lysine demethylase that removes di- and tri-methyl marks from H3K9 and H3K36 via an iron- and alpha-ketoglutarate-dependent hydroxylation reaction; it localizes to H3K4me3-positive transcription start sites through its Tudor domain (which stimulates catalysis in cis), associates with mitotic chromatin via Tudor domain residue R919 to regulate chromosome segregation, acts as a transcriptional co-activator by interacting with partners including HIF-1α, ATF4, β-catenin, and NF-κB p65, can demethylate non-histone substrates such as MyoD-K372 to control protein stability, is stabilized by deubiquitinase USP9X, and in specific contexts (KDM4C-amplified basal breast cancer) drives tumor suppression upon loss by triggering GRHL2 methylation-dependent cathepsin L histone H3 cleavage rather than through its canonical H3K9/H3K36 demethylase activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KDM4C (GASC1/JMJD2C) is a Jumonji-C domain histone lysine demethylase that erases di- and tri-methyl marks from H3K9 (and H3K36) through an iron- and alpha-ketoglutarate-dependent hydroxylation reaction, thereby converting repressive heterochromatin into transcriptionally permissive chromatin and displacing HP1 [#0]. Its substrate engagement is guided by a double Tudor domain that recognizes H3K4me3 at transcription start sites and stimulates H3K9me3 demethylation in cis, enforcing mutual exclusion of the two marks [#7, #11]; the Tudor domain also tethers KDM4C to mitotic chromatin via residue R919, where catalytic activity is required for faithful chromosome segregation [#8]. Through these activities KDM4C functions as a transcriptional co-activator recruited by sequence-specific factors—including HIF-1\\u03b1, ATF4, \\u03b2-catenin, and NF-\\u03baB p65—to demethylate H3K9 at target promoters and enhancers and activate gene programs governing hypoxia, amino-acid metabolism, proliferation, and stem-cell identity [#3, #12, #4, #23]. In pluripotency, it is an Oct4-induced regulator that demethylates the Nanog promoter and acts as a scaffold for enhancer assembly, and it partitions distinct genomic targets from KDM4B during reprogramming [#1, #4, #6]. KDM4C activity extends to non-histone substrates: it demethylates and stabilizes MyoD by blocking G9a-driven ubiquitination [#13] and demethylates p53-K372me1 to restrain its pro-apoptotic function [#19]. The enzyme is stabilized by the deubiquitinase USP9X [#18] and its catalysis is tuned by metabolite levels, being inhibited by inositol pyrophosphate (IP7) and by fumarate competing with alpha-ketoglutarate [#10, #38]. Across diverse cancers KDM4C behaves predominantly as an oncogenic dependency driving metastasis, stemness, and therapy resistance [#3, #17, #31], but it can act as a tumor suppressor whose loss is selected for in B-cell lymphoma [#41], and in KDM4C-amplified basal breast cancer its inhibition triggers a non-canonical, demethylase-independent program in which GRHL2 methylation recruits cathepsin L to cleave histone H3 and elevate reactive oxygen species [#29].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the founding biochemical identity of KDM4C: that it is an iron/alpha-ketoglutarate-dependent enzyme capable of erasing the repressive H3K9me3/me2 marks, defining a new mechanism for active heterochromatin removal.\",\n      \"evidence\": \"In vitro demethylase assay with defined cofactors plus ectopic expression with HP1 delocalization in cells\",\n      \"pmids\": [\"16732293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how the enzyme is recruited to specific loci\", \"Genome-wide target spectrum not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Placed KDM4C in the pluripotency network by showing it is an Oct4-induced demethylase that activates Nanog, answering how H3K9 demethylation maintains stem-cell self-renewal.\",\n      \"evidence\": \"RNAi knockdown, ChIP at Nanog promoter, and ES cell differentiation assays\",\n      \"pmids\": [\"17938240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect recruitment to Nanog promoter not dissected\", \"Did not address non-histone roles\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Quantified KDM4C substrate selectivity for H3K9me3 and demonstrated inhibitor discrimination from related Jumonji enzymes despite shared active-site topology, establishing it as a tractable selective target.\",\n      \"evidence\": \"In vitro enzyme kinetics and inhibitor selectivity assays\",\n      \"pmids\": [\"21575637\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity tested against a single comparator (KDM6A)\", \"No cellular validation of inhibitor selectivity\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved the recruitment logic of KDM4C, showing its double Tudor domain reads H3K4me3 (distinct from KDM4A/B specificity) to position the enzyme at active transcription start sites.\",\n      \"evidence\": \"In vitro Tudor binding assays, ChIP-seq, knockout mice, and siRNA in carcinoma cells\",\n      \"pmids\": [\"24396064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Modest global H3K9me3/H3K36me3 changes left the catalytic contribution at most loci unclear\", \"Did not connect TSS binding to catalysis mechanistically\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended KDM4C function beyond transcription to mitotic fidelity, mapping mitotic chromatin association to Tudor residue R919 and showing catalytic activity is required to prevent chromosome missegregation.\",\n      \"evidence\": \"Live-cell imaging, point-mutant and catalytic-dead overexpression, siRNA, and mitotic error scoring\",\n      \"pmids\": [\"24728997\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The relevant mitotic substrate or chromatin region was not identified\", \"How R919 binding couples to catalysis during mitosis unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided the mechanistic link between Tudor reading and catalysis, showing H3K4me3 recognition stimulates in-cis H3K9me3 demethylation, explaining mutual exclusion of the two marks.\",\n      \"evidence\": \"In vitro demethylase assays on peptide and mononucleosome substrates with kinetic and TTD-binding quantification\",\n      \"pmids\": [\"26747609\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cis stimulation not validated on native polynucleosome arrays in cells\", \"Quantitative contribution to genome-wide demethylation not measured\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined KDM4C as a transcription-factor-recruited co-activator, showing HIF-1\\u03b1 (not HIF-2\\u03b1) tethers it to hypoxia response elements to demethylate H3K9 and drive a pro-metastatic gene program.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP, gene expression, and knockdown xenograft/metastasis models\",\n      \"pmids\": [\"23129632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of HIF-1\\u03b1 versus HIF-2\\u03b1 selectivity not defined\", \"Whether catalysis is strictly required at all HRE targets not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed a scaffolding role independent of and complementary to catalysis, showing KDM4C is needed to load G9a, Mediator, and cohesin at priming enhancers, and partitions targets from KDM4B during reprogramming.\",\n      \"evidence\": \"Knockout ESCs, ChIP-seq co-occupancy, RNAi screen, and iPSC reprogramming assays\",\n      \"pmids\": [\"28087629\", \"24361252\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct protein contacts mediating scaffold assembly not mapped\", \"Catalytic versus structural contributions at enhancers not separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated KDM4C acts on non-histone substrates and controls protein stability, demethylating MyoD to block G9a-driven ubiquitination and stabilize it.\",\n      \"evidence\": \"GST pull-down, Co-IP, in vitro demethylation, ubiquitination, and myogenic conversion assays\",\n      \"pmids\": [\"26149774\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Demethylated MyoD residue(s) not precisely defined in the synthesis\", \"Generality of non-histone demethylation to other lineage factors unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected KDM4C to metabolic gene control, showing it activates and partners with ATF4 to upregulate serine-glycine biosynthesis and amino-acid transport, raising intracellular amino-acid levels.\",\n      \"evidence\": \"ChIP, Co-IP, metabolomics, and siRNA knockdown\",\n      \"pmids\": [\"26774480\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ATF4 interaction is direct or chromatin-templated not resolved\", \"Feedback between metabolite availability and KDM4C catalysis not tested here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Positioned KDM4C upstream of RNA m6A regulation, showing it opens chromatin at the ALKBH5 locus to drive leukemia stem-cell maintenance, integrating histone and RNA epigenetic layers.\",\n      \"evidence\": \"ChIP, ATAC-seq, shRNA, xenograft LSC assays, and m6A analysis\",\n      \"pmids\": [\"32402251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcription factors recruiting KDM4C to the ALKBH5 locus only partly defined\", \"Whether the same axis operates outside AML not addressed here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified post-translational control of KDM4C abundance, showing the deubiquitinase USP9X stabilizes it to sustain TGF-\\u03b22/Smad signaling and radioresistance.\",\n      \"evidence\": \"Tandem affinity purification, Co-IP, ubiquitination assay, ChIP, and xenografts\",\n      \"pmids\": [\"33558705\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin ligase opposing USP9X on KDM4C not identified\", \"Lysine residues ubiquitinated on KDM4C not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed KDM4C restrains tumor suppression by demethylating p53-K372me1 while activating c-Myc, broadening its non-histone substrate repertoire to a key tumor suppressor.\",\n      \"evidence\": \"Catalytic-dead rescue, ChIP, apoptosis assays, and glioblastoma models\",\n      \"pmids\": [\"33462212\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study without independent confirmation of p53-K372 demethylation\", \"Direct enzyme-substrate kinetics on p53 not reported\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered a demethylase-independent, context-specific tumor-suppressive vulnerability, showing that in KDM4C-amplified basal breast cancer its inhibition methylates GRHL2-K453, recruiting cathepsin L to cleave histone H3 and elevate ROS.\",\n      \"evidence\": \"CRISPR KO, proteomics, chromatin fractionation, CTSL activity assays, and genetic rescue\",\n      \"pmids\": [\"40457074\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzyme responsible for GRHL2-K453 methylation upon KDM4C loss not pinned down\", \"Generalizability beyond KDM4C-amplified basal context unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated metabolite-driven regulation of KDM4C, showing fumarate competes with alpha-ketoglutarate to inhibit catalysis, raising H3K36me3 and activating IL-6/JAK/STAT3 and immune-checkpoint gene expression in FH-deficient cancer.\",\n      \"evidence\": \"In vitro activity assay with fumarate, ChIP-qPCR, RNA-seq, and FH-knockdown models\",\n      \"pmids\": [\"40975760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative selectivity of fumarate inhibition among KDM4 paralogs not established\", \"Single-lab finding awaiting independent confirmation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved when KDM4C acts as an oncogenic dependency versus a tumor suppressor, and what dictates the switch between its canonical H3K9/H3K36 demethylase activity and non-canonical catalytic-independent functions.\",\n      \"evidence\": \"No single study in the corpus reconciles the opposing context-dependent roles\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying model for context-dependent oncogene/tumor-suppressor behavior\", \"Determinants selecting histone versus non-histone substrates not defined\", \"In vivo physiological (non-cancer) functions largely uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [13, 19]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 42]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [7, 11]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 12, 23]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 15]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 7, 11]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 3, 12]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 4, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 17, 29]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HIF1A\", \"ATF4\", \"CTNNB1\", \"RELA\", \"MYOD1\", \"USP9X\", \"SIRT1\", \"GATA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}