Affinage

KDM4C

Lysine-specific demethylase 4C · UniProt Q9H3R0

Length
1056 aa
Mass
120.0 kDa
Annotated
2026-06-10
98 papers in source corpus 43 papers cited in narrative 44 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2006 High

    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

    PMID:16732293

    Open questions at the time
    • Did not resolve how the enzyme is recruited to specific loci
    • Genome-wide target spectrum not defined
  2. 2007 High

    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

    PMID:17938240

    Open questions at the time
    • Direct versus indirect recruitment to Nanog promoter not dissected
    • Did not address non-histone roles
  3. 2011 Medium

    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

    PMID:21575637

    Open questions at the time
    • Selectivity tested against a single comparator (KDM6A)
    • No cellular validation of inhibitor selectivity
  4. 2014 High

    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

    PMID:24396064

    Open questions at the time
    • Modest global H3K9me3/H3K36me3 changes left the catalytic contribution at most loci unclear
    • Did not connect TSS binding to catalysis mechanistically
  5. 2014 High

    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

    PMID:24728997

    Open questions at the time
    • The relevant mitotic substrate or chromatin region was not identified
    • How R919 binding couples to catalysis during mitosis unknown
  6. 2016 High

    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

    PMID:26747609

    Open questions at the time
    • In-cis stimulation not validated on native polynucleosome arrays in cells
    • Quantitative contribution to genome-wide demethylation not measured
  7. 2013 High

    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

    PMID:23129632

    Open questions at the time
    • Determinants of HIF-1α versus HIF-2α selectivity not defined
    • Whether catalysis is strictly required at all HRE targets not established
  8. 2013 High

    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

    PMID:24361252 PMID:28087629

    Open questions at the time
    • Direct protein contacts mediating scaffold assembly not mapped
    • Catalytic versus structural contributions at enhancers not separated
  9. 2015 High

    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

    PMID:26149774

    Open questions at the time
    • Demethylated MyoD residue(s) not precisely defined in the synthesis
    • Generality of non-histone demethylation to other lineage factors unknown
  10. 2016 High

    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

    PMID:26774480

    Open questions at the time
    • Whether ATF4 interaction is direct or chromatin-templated not resolved
    • Feedback between metabolite availability and KDM4C catalysis not tested here
  11. 2020 High

    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

    PMID:32402251

    Open questions at the time
    • Direct transcription factors recruiting KDM4C to the ALKBH5 locus only partly defined
    • Whether the same axis operates outside AML not addressed here
  12. 2021 High

    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

    PMID:33558705

    Open questions at the time
    • Ubiquitin ligase opposing USP9X on KDM4C not identified
    • Lysine residues ubiquitinated on KDM4C not mapped
  13. 2021 Medium

    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

    PMID:33462212

    Open questions at the time
    • Single-lab study without independent confirmation of p53-K372 demethylation
    • Direct enzyme-substrate kinetics on p53 not reported
  14. 2025 High

    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

    PMID:40457074

    Open questions at the time
    • Enzyme responsible for GRHL2-K453 methylation upon KDM4C loss not pinned down
    • Generalizability beyond KDM4C-amplified basal context unknown
  15. 2025 Medium

    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

    PMID:40975760

    Open questions at the time
    • Quantitative selectivity of fumarate inhibition among KDM4 paralogs not established
    • Single-lab finding awaiting independent confirmation

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 3 GO:0016491 oxidoreductase activity 2 GO:0042393 histone binding 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0016787 hydrolase activity 1
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 2 GO:0005654 nucleoplasm 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1640170 Cell Cycle 1
Partners
ATF4CTNNB1GATA1HIF1AMYOD1RELASIRT1USP9X

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 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. In vitro demethylase assay with iron/alpha-KG cofactors; ectopic expression in cells with chromatin analysis; HP1 delocalization assay Nature High 16732293
2007 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. RNAi knockdown; ChIP assay at Nanog promoter; gene expression analysis; ES cell differentiation assay Genes & Development High 17938240
2009 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. ChIP assay; overexpression and siRNA knockdown; Western blot for p53 and Mdm2 Biochemical and Biophysical Research Communications Medium 19732750
2012 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. Co-immunoprecipitation; ChIP; knockdown with xenograft tumor model; gene expression analysis Proceedings of the National Academy of Sciences of the United States of America High 23129632
2013 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. Jmjd2c knockout ESCs; ChIP-seq; co-occupancy analysis; differentiation assays Development High 28087629
2013 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. ChIP; siRNA knockdown; colonosphere formation assay; microarray gene expression Carcinogenesis Medium 23698634
2013 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. RNAi screen; genome-wide ChIP-seq occupancy; iPSC reprogramming assay; double knockdown Molecular Cell High 24361252
2014 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. Jmjd2c knockout mice; ChIP-seq; in vitro Tudor domain binding assay; siRNA knockdown in carcinoma cells Molecular and Cellular Biology High 24396064
2014 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. Live-cell imaging; immunofluorescence; point mutant overexpression; siRNA knockdown; mitotic error scoring Nucleic Acids Research High 24728997
2014 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. Co-immunoprecipitation; siRNA knockdown; proliferation and clonogenic assays; Western blot American Journal of Translational Research Medium 24936217
2013 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. Co-immunoprecipitation; IP6K1 RNAi and knockout MEFs; chromatin fractionation; histone modification analysis; gene expression assay Proceedings of the National Academy of Sciences of the United States of America Medium 24191012
2016 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. In vitro demethylase assay with peptide and mononucleosome substrates; quantitative TTD binding assays; kinetic analysis The Journal of Biological Chemistry High 26747609
2016 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. ChIP; co-immunoprecipitation; metabolomics; siRNA knockdown; gene expression analysis Cell Reports High 26774480
2015 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. GST pull-down; co-immunoprecipitation; in vitro demethylation assay; ubiquitination assay; myogenic conversion assay; ChIP Biochimica et Biophysica Acta High 26149774
2015 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. ChIP; siRNA knockdown; endothelial differentiation assay; tube formation assay; zebrafish vasculogenesis model Stem Cell Reports Medium 26120059
2019 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. ChIP-PCR; luciferase reporter assay; siRNA knockdown/overexpression; Western blot; in vivo metastasis model Journal of Experimental & Clinical Cancer Research Medium 31665047
2019 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. ChIP; siRNA reprogramming in isolated endothelial cells and aortas; genetic manipulation in obese mice; ROS/NO measurement European Heart Journal Medium 29077881
2020 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. ChIP; ATAC-seq; siRNA/shRNA knockdown; xenograft leukemia stem cell assays; RNA m6A analysis Cell Stem Cell High 32402251
2021 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. Tandem affinity purification; co-immunoprecipitation; ChIP; ubiquitination assay; siRNA knockdown; xenograft model Cell Death and Differentiation High 33558705
2021 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. Catalytic dead mutant rescue experiment; ChIP; Western blot; apoptosis assay; in vitro and in vivo glioblastoma models Cell Death & Disease Medium 33462212
2021 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. ChIP; co-immunoprecipitation; siRNA knockdown; xenograft model Cancer Letters Medium 34265399
2019 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. siRNA/shRNA knockdown; overexpression; ChIP; DNA damage assays; Kdm3a-/- mouse model iScience Medium 31704649
2022 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. ChIP-PCR; RNA-seq; flow cytometry; in vivo mouse tumor model; pharmacological inhibitor SD70 Journal for Immunotherapy of Cancer Medium 35121645
2018 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. ChIP-seq; de novo motif analysis; co-immunoprecipitation; siRNA knockdown; B cell proliferation assay Nucleic Acids Research Medium 29718303
2014 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. Phage display screening; H/D exchange mass spectrometry; in vitro inhibition assays; peptide SAR ACS Chemical Biology Medium 25014588
2021 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. siRNA knockdown; ubiquitination assay; ChIP; demethylase inhibitor treatment; xenograft model Cell Death & Disease Medium 33692332
2023 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. ChIP; siRNA knockdown; overexpression rescue; in vivo MCAO mouse model The European Journal of Neuroscience Medium 37161649
2022 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. Genetic inactivation (CRISPR); xenograft models; histone methylation analysis; gene expression; senescence assays Leukemia Medium 35654819
2023 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. Chromatin immunoprecipitation; shRNA knockdown; proliferation assays in JAK2V617F and transgenic mouse models Leukemia Medium 36709354
2025 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. CRISPR KO; proteomics; chromatin fractionation; CTSL activity assays; rescue experiments; transcriptomic analysis Nature Genetics High 40457074
2026 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. Proximity labeling (BioID); CRISPR/Cas9 deletion; transcriptomic and proteomic analysis; in vivo orthotopic allograft model; phospho-ERK measurement Cancer Research Communications Medium 41490602
2019 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. ChIP; siRNA/shRNA knockdown; lentiviral overexpression rescue; ALDH+ cell sorting; in vivo xenograft Journal of Oncology Medium 31031809
2015 KDM4C demethylase activity is required for expression of FGF2 in osteosarcoma; GST pull-down showed JMJD2C interacts with FGF2 protein. GST pull-down; siRNA knockdown; Western blot; RT-PCR Medical Oncology Low 25636512
2024 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. ChIP-qPCR; overexpression/knockdown; RNA m6A quantification; in vivo CCl4 fibrosis model; Western blot Journal of Digestive Diseases Medium 38938016
2025 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. Co-immunoprecipitation; molecular docking; RNA-seq; CUT&Tag-seq; siRNA knockdown; zebrafish and mouse xenograft models Cellular and Molecular Life Sciences Medium 40259045
2025 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. Co-immunoprecipitation; GST pull-down; shRNA knockdown; tumor xenograft model Cancer Biology & Therapy Medium 38975736
2025 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. Lentiviral overexpression; RNA-seq; BrdU/Ki-67 staining; ApoE siRNA knockdown FASEB Journal Medium 38421303
2025 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. ChIP; siRNA overexpression/knockdown; co-immunoprecipitation; in vivo L-NAME-induced PE rat model; immunohistochemistry International Journal of Biological Macromolecules Medium 40716534
2025 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. In vitro KDM4C activity assay with fumarate; ChIP-qPCR; siRNA knockdown; in vivo FH-knockdown models; RNA-seq British Journal of Cancer Medium 40975760
2025 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. KDM4C overexpression; clonogenic survival assay; DNA damage assay; apoptosis analysis; pharmacological inhibitor SD70; in vivo xenograft International Journal of Radiation Biology Medium 40711862
2025 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. Molecular-protein docking; cellular thermal shift assay (CETSA); ChIP; dual luciferase reporter; CRC organoids; Apc mouse model Acta Pharmaceutica Sinica B Medium 39807336
2023 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. Whole genome sequencing; RNA-seq; functional reconstitution in cell lines; focal homozygous deletion identification Haematologica Medium 35522148
2011 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. In vitro enzyme kinetics; inhibitor selectivity assay FEBS Letters Medium 21575637
2025 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. Phenotypic screen; biochemical interaction analysis; cGAS-STING activation assay; high-throughput small molecule screen with nucleosome substrates bioRxivpreprint Low

Source papers

Stage 0 corpus · 98 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. Nature 591 16732293
2007 Jmjd1a and Jmjd2c histone H3 Lys 9 demethylases regulate self-renewal in embryonic stem cells. Genes & development 416 17938240
2020 Leukemogenic Chromatin Alterations Promote AML Leukemia Stem Cells via a KDM4C-ALKBH5-AXL Signaling Axis. Cell stem cell 219 32402251
2012 Histone demethylase JMJD2C is a coactivator for hypoxia-inducible factor 1 that is required for breast cancer progression. Proceedings of the National Academy of Sciences of the United States of America 199 23129632
2000 Identification of a novel gene, GASC1, within an amplicon at 9p23-24 frequently detected in esophageal cancer cell lines. Cancer research 198 10987278
2009 Genomic amplification and oncogenic properties of the GASC1 histone demethylase gene in breast cancer. Oncogene 164 19784073
2016 KDM4C and ATF4 Cooperate in Transcriptional Control of Amino Acid Metabolism. Cell reports 132 26774480
2013 Distinct and combinatorial functions of Jmjd2b/Kdm4b and Jmjd2c/Kdm4c in mouse embryonic stem cell identity. Molecular cell 105 24361252
2008 Mucosa-associated lymphoid tissue lymphoma: novel translocations including rearrangements of ODZ2, JMJD2C, and CNN3. Clinical cancer research : an official journal of the American Association for Cancer Research 93 18927281
2021 USP9X-mediated KDM4C deubiquitination promotes lung cancer radioresistance by epigenetically inducing TGF-β2 transcription. Cell death and differentiation 76 33558705
2006 Molecular cytogenetic characterization of a metastatic lung sarcomatoid carcinoma: 9p23 neocentromere and 9p23-p24 amplification including JAK2 and JMJD2C. Cancer genetics and cytogenetics 73 16737911
2009 The histone demethylase JMJD2C is stage-specifically expressed in preimplantation mouse embryos and is required for embryonic development. Biology of reproduction 68 19696013
2014 The demethylase JMJD2C localizes to H3K4me3-positive transcription start sites and is dispensable for embryonic development. Molecular and cellular biology 66 24396064
2018 circZMYM2 Competed Endogenously with miR-335-5p to Regulate JMJD2C in Pancreatic Cancer. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 62 30537731
2014 Pro-growth role of the JMJD2C histone demethylase in HCT-116 colon cancer cells and identification of curcuminoids as JMJD2 inhibitors. American journal of translational research 60 24936217
2013 Inositol pyrophosphates regulate JMJD2C-dependent histone demethylation. Proceedings of the National Academy of Sciences of the United States of America 60 24191012
2019 Interplay among H3K9-editing enzymes SUV39H1, JMJD2C and SRC-1 drives p66Shc transcription and vascular oxidative stress in obesity. European heart journal 59 29077881
2019 JMJD2C promotes colorectal cancer metastasis via regulating histone methylation of MALAT1 promoter and enhancing β-catenin signaling pathway. Journal of experimental & clinical cancer research : CR 59 31665047
2022 Targeting KDM4C enhances CD8+ T cell mediated antitumor immunity by activating chemokine CXCL10 transcription in lung cancer. Journal for immunotherapy of cancer 54 35121645
2021 Histone demethylase KDM4C controls tumorigenesis of glioblastoma by epigenetically regulating p53 and c-Myc. Cell death & disease 51 33462212
2021 UHRF1 promotes androgen receptor-regulated CDC6 transcription and anti-androgen receptor drug resistance in prostate cancer through KDM4C-Mediated chromatin modifications. Cancer letters 49 34265399
2019 KDM3A and KDM4C Regulate Mesenchymal Stromal Cell Senescence and Bone Aging via Condensin-mediated Heterochromatin Reorganization. iScience 46 31704649
2009 Jmjd2c histone demethylase enhances the expression of Mdm2 oncogene. Biochemical and biophysical research communications 46 19732750
2015 Histone Demethylases KDM4A and KDM4C Regulate Differentiation of Embryonic Stem Cells to Endothelial Cells. Stem cell reports 45 26120059
2013 Histone demethylase KDM4C regulates sphere formation by mediating the cross talk between Wnt and Notch pathways in colonic cancer cells. Carcinogenesis 43 23698634
2018 The KDM4A/KDM4C/NF-κB and WDR5 epigenetic cascade regulates the activation of B cells. Nucleic acids research 37 29718303
2014 KDM4C (GASC1) lysine demethylase is associated with mitotic chromatin and regulates chromosome segregation during mitosis. Nucleic acids research 36 24728997
2001 A novel amplicon at 9p23 - 24 in squamous cell carcinoma of the esophagus that lies proximal to GASC1 and harbors NFIB. Japanese journal of cancer research : Gann 36 11346465
2007 Comparative integromics on JMJD2A, JMJD2B and JMJD2C: preferential expression of JMJD2C in undifferentiated ES cells. International journal of molecular medicine 34 17611647
2019 Histone Demethylase KDM4C Stimulates the Proliferation of Prostate Cancer Cells via Activation of AKT and c-Myc. Cancers 33 31766290
2015 Jmjd2C increases MyoD transcriptional activity through inhibiting G9a-dependent MyoD degradation. Biochimica et biophysica acta 33 26149774
2011 Genome-wide association study identifies 5q21 and 9p24.1 (KDM4C) loci associated with alcohol withdrawal symptoms. Journal of neural transmission (Vienna, Austria : 1996) 32 22072270
2010 Analysis of 9p24 and 11p12-13 regions in autism spectrum disorders: rs1340513 in the JMJD2C gene is associated with ASDs in Finnish sample. Psychiatric genetics 32 20410850
2016 Opposing Chromatin Signals Direct and Regulate the Activity of Lysine Demethylase 4C (KDM4C). The Journal of biological chemistry 30 26747609
2020 microRNA-216b enhances cisplatin-induced apoptosis in osteosarcoma MG63 and SaOS-2 cells by binding to JMJD2C and regulating the HIF1α/HES1 signaling axis. Journal of experimental & clinical cancer research : CR 29 32972441
2011 Regulation of adipogenesis by nuclear receptor PPARγ is modulated by the histone demethylase JMJD2C. Genetics and molecular biology 29 21637537
2024 Kaempferol inhibits colorectal cancer metastasis through circ_0000345 mediated JMJD2C/β-catenin signalling pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 28 38493716
2011 High-throughput TR-FRET assays for identifying inhibitors of LSD1 and JMJD2C histone lysine demethylases. Journal of biomolecular screening 27 21859682
2015 KDM4A, KDM4B and KDM4C in non-small cell lung cancer. International journal of clinical and experimental pathology 26 26722485
2023 Luteolin directly binds to KDM4C and attenuates ovarian cancer stemness via epigenetic suppression of PPP2CA/YAP axis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 25 36804120
2008 Polycythemia vera transforming to acute myeloid leukemia and complex abnormalities including 9p homogeneously staining region with amplification of MLLT3, JMJD2C, JAK2, and SMARCA2. Cancer genetics and cytogenetics 25 18068534
2018 Cross-phenotype analysis of Immunochip data identifies KDM4C as a relevant locus for the development of systemic vasculitis. Annals of the rheumatic diseases 24 29374629
2014 Substrate- and cofactor-independent inhibition of histone demethylase KDM4C. ACS chemical biology 24 25014588
2016 KDM4C Activity Modulates Cell Proliferation and Chromosome Segregation in Triple-Negative Breast Cancer. Breast cancer : basic and clinical research 23 27840577
2023 BACH1 encourages ferroptosis by activating KDM4C-mediated COX2 demethylation after cerebral ischemia-reperfusion injury. The European journal of neuroscience 22 37161649
2023 KDM4C-mediated senescence defense is a targetable vulnerability in gastric cancer harboring TP53 mutations. Clinical epigenetics 22 37848946
2017 Jmjd2c facilitates the assembly of essential enhancer-protein complexes at the onset of embryonic stem cell differentiation. Development (Cambridge, England) 22 28087629
2016 KDM4C, a H3K9me3 Histone Demethylase, is Involved in the Maintenance of Human ESCC-Initiating Cells by Epigenetically Enhancing SOX2 Expression. Neoplasia (New York, N.Y.) 21 27742014
2015 Histone demethylase JMJD2B and JMJD2C induce fibroblast growth factor 2: mediated tumorigenesis of osteosarcoma. Medical oncology (Northwood, London, England) 17 25636512
2022 JMJD2C-mediated long non-coding RNA MALAT1/microRNA-503-5p/SEPT2 axis worsens non-small cell lung cancer. Cell death & disease 16 35046387
2021 KDM4C contributes to cytarabine resistance in acute myeloid leukemia via regulating the miR-328-3p/CCND2 axis through MALAT1. Therapeutic advances in chronic disease 16 34394903
2011 Enzyme kinetic studies of histone demethylases KDM4C and KDM6A: towards understanding selectivity of inhibitors targeting oncogenic histone demethylases. FEBS letters 16 21575637
2022 Essential Roles of the Histone Demethylase KDM4C in Renal Development and Acute Kidney Injury. International journal of molecular sciences 15 36012577
2020 Rare genetic variants in the gene encoding histone lysine demethylase 4C (KDM4C) and their contributions to susceptibility to schizophrenia and autism spectrum disorder. Translational psychiatry 15 33279929
2021 GASC1 promotes hepatocellular carcinoma progression by inhibiting the degradation of ROCK2. Cell death & disease 14 33692332
2023 KDM4C silencing inhibits cell migration and enhances radiosensitivity by inducing CXCL2 transcription in hepatocellular carcinoma. Cell death discovery 12 37117173
2021 GASC1 promotes glioma progression by enhancing NOTCH1 signaling. Molecular medicine reports 11 33649841
2019 GASC1 Promotes Stemness of Esophageal Squamous Cell Carcinoma via NOTCH1 Promoter Demethylation. Journal of oncology 11 31031809
2019 Rational design, synthesis and biological profiling of new KDM4C inhibitors. Bioorganic & medicinal chemistry 11 31784197
2017 Histone demethylase JMJD2C: epigenetic regulators in tumors. Oncotarget 11 29207681
2024 Synergistic effects of the KDM4C inhibitor SD70 and the menin inhibitor MI-503 against MLL::AF9-driven acute myeloid leukaemia. British journal of haematology 10 38877874
2022 Histone demethylase KDM4C is a functional dependency in JAK2-mutated neoplasms. Leukemia 10 35654819
2020 Histone demethylase KDM4C activates HIF1α/VEGFA signaling through the costimulatory factor STAT3 in NSCLC. American journal of cancer research 10 32195022
2015 The oncogenic role of GASC1 in chemically induced mouse skin cancer. Mammalian genome : official journal of the International Mammalian Genome Society 10 26248577
2022 JMJD2C mediates the MDM2/p53/IL5RA axis to promote CDDP resistance in uveal melanoma. Cell death discovery 8 35468881
2021 JMJD2C triggers the growth of multiple myeloma cells via activation of β‑catenin. Oncology reports 8 33469678
2020 Histone Demethylase KDM4C Is Required for Ovarian Cancer Stem Cell Maintenance. Stem cells international 8 32908544
2024 The promotive role of lncRNA MIR205HG in proliferation, invasion, and migration of melanoma cells via the JMJD2C/ALKBH5 axis. PloS one 7 38252669
2024 KDM4C promotes mouse hippocampal neural stem cell proliferation through modulating ApoE expression. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 7 38421303
2024 Avenanthramide A potentiates Bim-mediated antineoplastic properties of 5-fluorouracil via targeting KDM4C/MIR17HG/GSK-3β negative feedback loop in colorectal cancer. Acta pharmaceutica Sinica. B 7 39807336
2023 The histone demethylase JMJD2C constitutes a novel NFE2 target gene that is required for the survival of JAK2V617F mutated cells. Leukemia 7 36709354
2021 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. Autoimmunity 7 34121556
2020 GASC1-Adapted Neoadjuvant Chemotherapy for Resectable Esophageal Squamous Cell Carcinoma: A Prospective Clinical Biomarker Trial. Journal of oncology 7 32411232
2025 KDM4C inhibition blocks tumor growth in basal breast cancer by promoting cathepsin L-mediated histone H3 cleavage. Nature genetics 6 40457074
2023 Focal structural variants revealed by whole genome sequencing disrupt the histone demethylase KDM4C in B-cell lymphomas. Haematologica 6 35522148
2017 Reduced Histone H3 Lysine 9 Methylation Contributes to the Pathogenesis of Latent Autoimmune Diabetes in Adults via Regulation of SUV39H2 and KDM4C. Journal of diabetes research 6 28396876
2024 KDM4C represses liver fibrosis by regulating H3K9me3 methylation of ALKBH5 and m6A methylation of snail1 mRNA. Journal of digestive diseases 5 38938016
2021 Novel germline variant in the histone demethylase and transcription regulator KDM4C induces a multi-cancer phenotype. Journal of medical genetics 5 34281993
2018 Kdm4c is Recruited to Mitotic Chromosomes and Is Relevant for Chromosomal Stability, Cell Migration and Invasion of Triple Negative Breast Cancer Cells. Breast cancer : basic and clinical research 5 30083054
2016 Post-Transcriptional Regulation of the GASC1 Oncogene with Active Tumor-Targeted siRNA-Nanoparticles. Molecular pharmaceutics 5 27223606
2024 Identification of KDM4C as a gene conferring drug resistance in multiple myeloma. Open life sciences 4 38623585
2024 KDM4C and GFPT1: Potential Therapeutic Targets for Gastric Cancer. Discovery medicine 4 39726315
2022 KDM4C Contributes to Trophoblast-like Stem Cell Conversion from Porcine-Induced Pluripotent Stem Cells (piPSCs) via Regulating CDX2. International journal of molecular sciences 4 35886932
2022 Histone Demethylase GASC1 Inhibitor Targeted GASC1 Gene to Inhibit the Malignant Transformation of Esophageal Cancer through the NOTCH-MAPK Signaling Pathway. Annals of clinical and laboratory science 3 35414503
2025 KDM4C works in concert with GATA1 to regulate heme metabolism in head and neck squamous cell carcinoma. Cellular and molecular life sciences : CMLS 2 40259045
2025 Targeted inhibition of JMJD2C/MALAT1 axis compensates for the deficiency of metformin in reversing ovarian cancer platinum resistance. Life sciences 2 40280301
2025 USP35 promotes hepatocellular carcinoma proliferation through GASC1-mediated ROCK2 upregulation. Translational oncology 2 40424935
2024 Jmjd2c maintains the ALDHbri+ cancer stemness with transcription factor SOX2 in lung squamous cell carcinoma. Cancer biology & therapy 2 38975736
2026 The Lysine Demethylase KDM4C Is an Oncogenic Driver and Regulates ERK Activity in KRAS-Mutant Pancreatic Ductal Adenocarcinoma. Cancer research communications 1 41490602
2026 Targeting epigenetic regulators: In-silico discovery of natural inhibitors against histone demethylase KDM4C. PloS one 1 41505486
2025 KDM4C regulates trophoblast proliferation and migration in preeclampsia via the NFATc4/Wnt pathway. International journal of biological macromolecules 1 40716534
2025 Fumarate activates the IL-6/JAK/STAT3 pathway by inhibiting KDM4C-mediated H3K36me3 demethylation in FH-knockdown renal cancer cells. British journal of cancer 1 40975760
2025 Histone demethylase KDM4C confers temozolomide resistance to glioblastoma cells by epigenetically regulating E2F6. Archives of pharmacal research 1 41217736
2026 Rare KDM4C variants and reduced expression underlie epigenetic dysregulation in rheumatoid arthritis. Immunologic research 0 41680357
2025 Targeting KDM4C Prevents Heart Failure after Acute Myocardial Infarction Via Activation of SOS2. Journal of cardiovascular translational research 0 39900886
2025 Mutation of the histone demethylase Gasc1 causes ASD-like symptoms in mice. Inflammation and regeneration 0 40635012
2025 Impact of KDM4C on the radiosensitivity of glioblastoma cells. International journal of radiation biology 0 40711862
2025 Luteolin Alleviates Diabetic Foot Ulcers Through Improving KDM4C/ITGA1-mediated Functional Impairments of AGEs-Induced Senescent Endothelial Cell. Journal of biochemical and molecular toxicology 0 40778546

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