Affinage

KDM4B

Lysine-specific demethylase 4B · UniProt O94953

Length
1096 aa
Mass
121.9 kDa
Annotated
2026-04-28
100 papers in source corpus 42 papers cited in narrative 42 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KDM4B is a JmjC-domain histone demethylase that catalyzes the removal of H3K9me3/me2 (and H3K36me3) at gene promoters, converting repressive heterochromatin into a transcriptionally permissive state to enable activation of target genes by diverse transcription factors including ERα, AR, β-catenin, c-Myc, N-Myc, GATA-3, C/EBPβ, NF-κB p65, and MyoD (PMID:16738407, PMID:21502505, PMID:21445275, PMID:24077348, PMID:34335964, PMID:34031372). KDM4B operates within multi-protein complexes—including the MLL2 H3K4 methyltransferase complex, SWI/SNF-B, and a KDM4B–CCAR1–MED1 module—where its H3K9 demethylation is a prerequisite for subsequent activating histone modifications and cofactor recruitment (PMID:21502505, PMID:21445275, PMID:34031372). Beyond its canonical histone demethylase role, KDM4B binds RNA and couples with splicing factor SF3B3 after PKA-mediated phosphorylation to promote AR-V7 splice variant inclusion, and interacts with cytoplasmic eIF2α to suppress the unfolded protein response (PMID:31647098, PMID:30266800). KDM4B protein stability is regulated by Hsp90 chaperoning, SCF-Fbxo22-mediated ubiquitination at K337/K562, UCHL1-mediated deubiquitination, and ERK-dependent phosphorylation that protects against proteasomal degradation (PMID:23589305, PMID:30418174, PMID:38743986, PMID:28945223).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2006 High

    Establishing that KDM4B is an active H3K9me3 demethylase resolved how trimethylated heterochromatic marks could be reversed enzymatically, demonstrating that Jmjd2b removes H3K9me3 at pericentric heterochromatin through active demethylation rather than passive dilution.

    Evidence Inducible Jmjd2b-GFP cell lines with heavy methyl metabolic labeling and immunofluorescence in mouse cells

    PMID:16738407

    Open questions at the time
    • Substrate specificity for H3K9 vs. H3K36 not fully delineated
    • No structural information on active site
    • In vivo physiological functions unknown
  2. 2008 High

    Demonstrating that HIF-1α directly transcribes KDM4B established a mechanism by which hypoxia remodels the epigenome, linking oxygen sensing to H3K9 demethylation.

    Evidence Reporter assays, ChIP showing HIF-1α at KDM4B promoter, demethylase activity under hypoxia

    PMID:18984585

    Open questions at the time
    • Downstream target genes in hypoxia not mapped
    • Whether KDM4B is rate-limiting for hypoxic gene activation unclear
  3. 2011 High

    Discovering that KDM4B is an integral subunit of the MLL2 complex and cooperates with ERα/SWI/SNF-B established that H3K9 demethylation is mechanistically ordered before H3K4 methylation at estrogen-responsive genes, defining the chromatin logic of ER-driven transcription.

    Evidence Co-purification of KDM4B with MLL2 and ERα, sequential ChIP showing H3K9me3 removal precedes H3K4 methylation, siRNA in breast cancer cells and mammary-specific KO mice

    PMID:21445275 PMID:21502505

    Open questions at the time
    • Whether KDM4B is constitutive or dynamically recruited to MLL2 unclear
    • Direct structural contacts within the complex not mapped
  4. 2012 High

    Showing that KDM4B promotes osteogenic differentiation by removing H3K9me3 at DLX promoters and acts as a C/EBPβ cofactor at cell-cycle gene promoters during adipogenesis established KDM4B as a lineage fate determinant in mesenchymal stem cells.

    Evidence ChIP, siRNA, differentiation assays in human MSCs and 3T3-L1 cells, ovariectomized mouse model

    PMID:22722334 PMID:22770241

    Open questions at the time
    • How KDM4B selects between osteogenic and adipogenic gene sets not resolved
    • Genome-wide target maps in differentiating MSCs lacking at this time
  5. 2013 High

    A series of 2013 studies simultaneously expanded KDM4B's mechanistic landscape: (1) dual catalytic and non-catalytic enhancement of AR signaling, (2) PARP1-dependent recruitment to DNA double-strand breaks, (3) Hsp90-dependent protein stability via ubiquitination at K337/K562, (4) p53-driven transcriptional induction creating an auto-regulatory loop, and (5) β-catenin interaction promoting EMT—collectively establishing KDM4B as a multi-pathway signaling hub.

    Evidence AR ubiquitination assays and siRNA screen (AR); laser micro-irradiation with live-cell imaging (DSB); Hsp90 Co-IP with site-directed mutagenesis (stability); p53 ChIP and catalytic dead mutant (p53 loop); Co-IP and ChIP at vimentin promoter with in vivo metastasis assay (β-catenin/EMT)

    PMID:23376847 PMID:23435229 PMID:23589305 PMID:23744078 PMID:24077348

    Open questions at the time
    • Whether DNA repair and transcription functions are mutually exclusive or concurrent unclear
    • Structural basis of Hsp90-KDM4B chaperoning not determined
    • p53 auto-regulatory loop kinetics not quantified
  6. 2014 High

    The crystal structure of KDM4B with H3K9me3 peptide revealed the molecular determinants of K9/K36 dual specificity and enabled structure-based inhibitor discovery, providing the first atomic-resolution view of this demethylase's catalytic mechanism.

    Evidence X-ray crystallography of KDM4B ternary complex, virtual screening yielding selective KDM4A/B inhibitor, enzymatic inhibition assays

    PMID:24971742

    Open questions at the time
    • Full-length structure not available
    • Structural basis of non-histone substrate recognition (eIF2α, RNA) unknown
    • No co-crystal with transcription factor partners
  7. 2015 High

    Demonstration that KDM4B is required for TGF-β-driven SOX9 activation (enabling SMAD3 occupancy) and for otic vesicle invagination via Dlx3 regulation established that KDM4B-mediated H3K9 demethylation is a gating step for transcription factor access at developmental loci in vivo.

    Evidence ChIP in MSCs with SMAD3 dependency; in vivo ChIP in chick embryo with catalytically dead mutant rescue

    PMID:26485430 PMID:26598618

    Open questions at the time
    • Whether KDM4B is universally required for SMAD3 chromatin access unclear
    • Developmental phenotypes in mammalian ear not confirmed
  8. 2016 High

    Neuron-specific KDM4B deletion causing spine maturation defects, hyperactivity, working memory deficits, and epileptic-like seizures established a requirement for H3K9me3 demethylation in CNS development and neural circuit function.

    Evidence Conditional cre-loxP knockout mice with spine morphology and behavioral analysis

    PMID:27023172

    Open questions at the time
    • Direct neuronal target genes of KDM4B not identified
    • Whether phenotype reflects developmental or ongoing adult function unclear
  9. 2017 High

    Identification of ERK-mediated phosphorylation sites (T305, S352, S566, T1065) that stabilize KDM4B under glucose deprivation, enabling GLUT1 epigenetic activation, established a nutrient-sensing post-translational control mechanism for KDM4B.

    Evidence Co-IP with p-ERK, phosphosite mapping, ChIP at GLUT1 promoter in cancer cells

    PMID:28945223

    Open questions at the time
    • In vivo metabolic significance of ERK-KDM4B axis not tested
    • Interplay between ERK and Hsp90 stabilization pathways unknown
  10. 2018 High

    Discovery that SCF-Fbxo22 ubiquitylates KDM4B specifically when complexed with tamoxifen-bound ERα resolved how SERM antagonism is executed at the chromatin level, and identification of a cytoplasmic KDM4B–eIF2α interaction suppressing UPR revealed a non-histone function.

    Evidence Ubiquitination assays and live-cell imaging for Fbxo22–KDM4B–ERα; Co-IP with catalytic mutant for eIF2α interaction

    PMID:30266800 PMID:30418174

    Open questions at the time
    • Whether KDM4B demethylates eIF2α directly or acts via scaffolding not determined
    • Fbxo22 specificity for KDM4B over other KDM4 family members not fully explored
  11. 2019 High

    Demonstrating that PKA-phosphorylated KDM4B binds RNA and couples with splicing factor SF3B3 to promote AR-V7 exon inclusion fundamentally expanded KDM4B's functional repertoire beyond histone demethylation to co-transcriptional splicing regulation.

    Evidence RNA binding assays, chromatin accessibility profiling, genome-wide KDM4B RNA binding, splice isoform analysis in prostate cancer cells

    PMID:31647098

    Open questions at the time
    • RNA binding specificity and structural basis not characterized
    • Whether RNA-binding function is relevant beyond AR-V7 not tested genome-wide for functional splicing changes
  12. 2021 High

    Multiple 2021 studies expanded KDM4B's role to skeletal homeostasis (KDM4B–CCAR1–MED1 complex recruiting NF-κB p65 for osteoclastogenesis; KDM4B required for PTH bone anabolism), ALT telomere maintenance (KDM4B inactivation promotes ALT), and AML (KDM4B maintaining chromatin accessibility at AML1-ETO sites)—revealing tissue-specific complex assembly as the basis for KDM4B's diverse functions.

    Evidence ChIP-seq, Co-IP, myeloid- and mesenchymal-specific conditional KO mice with skeletal phenotypes; mouse ESC quadruple KO for ALT; ATAC-seq with domain mutants and conditional KO in AML models

    PMID:33571444 PMID:33972520 PMID:34031372 PMID:34938963

    Open questions at the time
    • How KDM4B distinguishes between osteoblast and osteoclast gene programs unclear
    • Whether ALT suppression requires catalytic activity or reader domains not fully separated
    • KDM4B-CCAR1-MED1 stoichiometry and assembly mechanism unknown
  13. 2023 Medium

    Identification of m6A-mediated stabilization of KDM4B mRNA through the HIF1α–WTAP axis in AML revealed a post-transcriptional layer of KDM4B regulation linking epitranscriptomic and epigenomic circuits.

    Evidence m6A-seq, mRNA stability assays, HIF1α ChIP at WTAP promoter, KDM4B knockdown in leukemia cells and mice

    PMID:37087529

    Open questions at the time
    • Specific m6A sites on KDM4B mRNA not mapped to single-nucleotide resolution
    • Whether m6A regulation of KDM4B extends beyond AML context not tested
    • Single-lab finding
  14. 2024 Medium

    Discovery that UCHL1 deubiquitinates and stabilizes KDM4B, which then cooperates with HIF2α at the VEGFA promoter, identified a deubiquitinase–demethylase axis in renal cell carcinoma angiogenesis.

    Evidence In vivo ubiquitination assays with UCHL1 catalytic mutant, ChIP at VEGFA promoter, Co-IP

    PMID:38743986

    Open questions at the time
    • Whether UCHL1 directly deubiquitinates K337/K562 identified earlier not tested
    • Relationship to Fbxo22-mediated ubiquitination not integrated
    • Single-lab study

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis for KDM4B's RNA binding and non-histone substrate recognition; how tissue-specific transcription factor partnerships are prioritized; the full-length structure of KDM4B in complex with its partner assemblies; and whether KDM4B's catalytic and non-catalytic functions are separable in vivo across developmental and disease contexts.
  • No full-length KDM4B structure
  • RNA-binding domain not structurally mapped
  • Genome-wide non-histone substrate landscape unknown
  • In vivo separation of catalytic vs. scaffolding functions not achieved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 13 GO:0140110 transcription regulator activity 5 GO:0042393 histone binding 3 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 6 GO:0000228 nuclear chromosome 3 GO:0005829 cytosol 1
Pathway
R-HSA-4839726 Chromatin organization 11 R-HSA-162582 Signal Transduction 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1266738 Developmental Biology 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-73894 DNA Repair 1 R-HSA-8953854 Metabolism of RNA 1
Partners
ARCEBPBCTNNB1ESR1GATA3HSP90AA1MYCRELA
Complex memberships
JMJD2B-TFAP2C-LSD1 complexKDM4B-CCAR1-MED1 complexMLL2 complexSWI/SNF-B complex

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Murine Jmjd2b (KDM4B ortholog) actively removes H3K9me3 at pericentric heterochromatin; metabolic labeling with heavy methyl groups demonstrated this is an active demethylation process occurring before replication. Jmjd2b also reduces H3K36 methylation. Inducible Jmjd2b-GFP cell lines, metabolic labeling with heavy methyl groups, immunofluorescence Genes & development High 16738407
2008 HIF-1α directly binds to recognition sites in the JMJD2B (KDM4B) gene and induces its expression under hypoxia; JMJD2B retains histone lysine demethylase activity in hypoxic conditions. Reporter assays, chromatin immunoprecipitation, ectopic expression with demethylase activity assays The Journal of biological chemistry High 18984585
2011 JMJD2B (KDM4B) is an integral component of the MLL2 H3K4 methyltransferase complex and co-purifies with estrogen receptor α (ERα); JMJD2B-mediated H3K9 demethylation is a prerequisite for H3K4 methylation at ERα target genes, coordinating these opposing histone marks during transcriptional activation. Co-purification/Co-IP of MLL2 complex, ChIP, siRNA knockdown, in vitro and in vivo proliferation assays Proceedings of the National Academy of Sciences of the United States of America High 21502505
2011 JMJD2B (KDM4B) interacts with ERα and components of the SWI/SNF-B chromatin remodeling complex; it is recruited to ERα target sites where it demethylates H3K9me3 to facilitate transcription of ER-responsive genes including MYB, MYC, and CCND1. Co-immunoprecipitation, ChIP, siRNA knockdown, mammary gland-specific knockout mouse PloS one High 21445275
2012 KDM4B promotes osteogenic differentiation of human MSCs by removing H3K9me3 at DLX gene promoters; KDM6B acts in parallel by removing H3K27me3. Loss of KDM4B reduces osteogenic and increases adipogenic differentiation. siRNA knockdown, ChIP, differentiation assays, ovariectomized and aging mouse models Cell stem cell High 22770241
2012 Kdm4b functions as a co-factor of C/EBPβ during mitotic clonal expansion (MCE) of 3T3-L1 preadipocytes: C/EBPβ directly binds and activates the Kdm4b promoter, Kdm4b interacts with C/EBPβ, is recruited to promoters of cell cycle genes (Cdc45l, Mcm3, Gins1, Cdc25c), demethylates H3K9me3, and activates their transcription. ChIP-on-chip, EMSA, luciferase assay, Co-IP, siRNA knockdown, gene expression microarrays Cell death and differentiation High 22722334
2013 KDM4B enzymatic demethylase activity is required to enhance androgen receptor (AR) transcriptional activity; independently of demethylase activity, KDM4B also enhances AR protein stability by inhibiting AR ubiquitination. KDM4B knockdown nearly completely depletes AR protein levels. siRNA screen, enzymatic activity assays, ubiquitination assays, multiple prostate cancer cell lines Nucleic acids research High 23435229
2013 KDM4B controls expression of estrogen receptor (ER) and FOXA1 by removing H3K9me3 at their upstream regulatory regions; KDM4B interacts with transcription factor GATA-3 and co-activates GATA-3 activity, permitting GATA-3 binding to the ER gene promoter. Co-IP, reporter assays, ChIP, siRNA knockdown in breast cancer cell lines Nucleic acids research High 23723241
2013 Kdm4b is rapidly recruited to DNA double-strand breaks induced by laser micro-irradiation in a PARP1 activity-dependent and demethylase activity-dependent manner. Kdm4b overexpression decreases γH2AX foci 6 h post-irradiation and increases cell survival after γ-irradiation; global H3K9me2/3 levels are decreased early after irradiation. Live-cell laser micro-irradiation, EGFP-Kdm4b recruitment assays, PARP1 inhibition, γH2AX immunofluorescence, clonogenic survival assay The Journal of biological chemistry High 23744078
2013 Jmjd2b and Jmjd2c (KDM4B and KDM4C) are necessary for self-renewal of mouse ESCs; Jmjd2b unique target sites belong to the Core regulatory module (associated with pluripotency factors) and Jmjd2b and Nanog act through an interconnected regulatory loop. RNAi screen, genome-wide ChIP-seq occupancy, iPSC generation assays Molecular cell High 24361252
2013 JMJD2B (KDM4B) is physically associated with β-catenin and enhances its nuclear localization and transcriptional activity; JMJD2B together with β-catenin binds to the vimentin promoter and increases its transcription via local H3K9 demethylation to promote EMT in gastric cancer. Co-IP, ChIP, siRNA knockdown, invasion and migration assays, in vivo metastasis assay Clinical cancer research High 24077348
2013 Hsp90 interacts with and stabilizes KDM4B protein; pharmacological inhibition of Hsp90 with geldanamycin causes ubiquitin-dependent proteasomal degradation of KDM4B (but not KDM4C). KDM4B is ubiquitinated on lysines 337 and 562; simultaneous K337R/K562R substitution suppresses geldanamycin-induced degradation. Co-IP, geldanamycin treatment, ubiquitination assays, site-directed mutagenesis, proteasome inhibitor experiments The Journal of biological chemistry High 23589305
2013 p53 directly induces JMJD2B (KDM4B) expression by binding to a canonical p53-consensus motif in the JMJD2B promoter after DNA damage. JMJD2B induction attenuates transcription of p53 targets including p21 and PUMA in a catalytic capacity-dependent manner, creating an auto-regulatory loop. Promoter binding assays, ChIP, catalytically dead JMJD2B mutant, siRNA knockdown Oncogene High 23376847
2014 Crystal structure of KDM4B in ternary complex with pyridine 2,4-dicarboxylic acid and H3K9me3 peptide reveals the core active-site region and a selective K9/K36 recognition site. Virtual screening identified a selective KDM4A/KDM4B inhibitor occupying three subsites. X-ray crystallography, virtual screening, enzymatic inhibition assays, prostate cancer cell viability assays Journal of medicinal chemistry High 24971742
2014 KDM4B forms complexes with β-catenin (involving KDM4B amino acids 353-740) and with TCF4 in colon cancer cells; KDM4B downregulation reduces expression of β-catenin/TCF4 target genes JUN, MYC, and Cyclin D1. In vitro pulldown, Co-IP in vivo, siRNA knockdown, gene expression analysis International journal of oncology Medium 24481461
2014 KDM4B directly regulates CDK6 transcription via demethylation of H3K9 in the CDK6 promoter region, promoting G1/S transition in bladder and lung cancer cells. ChIP, siRNA knockdown, cell cycle analysis, clonogenicity assay with catalytic mutant Cancer prevention research Medium 21930796
2015 TGF-β induces KDM4B expression in MSCs; upon TGF-β stimulation, KDM4B is recruited to the SOX9 promoter, removes H3K9me3, activates SOX9 transcription, and is required for SMAD3 occupancy at the SOX9 promoter for chondrogenic differentiation. ChIP, shRNA knockdown, overexpression, SMAD3 ChIP in KDM4B-depleted cells Stem cells High 26485430
2015 KDM4B interacts with and is recruited by N-Myc; KDM4B regulates neuroblastoma cell proliferation and differentiation in vitro and xenograft growth in vivo as a component of Myc pathway regulation. Co-immunoprecipitation, immunofluorescence, ChIP, lentiviral shRNA knockdown, xenograft models Journal of the National Cancer Institute Medium 25925418
2015 KDM4B regulates otic vesicle invagination in chick by directly occupying and removing H3K9me3 at the Dlx3 locus; a catalytically dead KDM4B mutant fails to rescue the invagination phenotype caused by KDM4B knockdown. In vivo ChIP in chick embryo, catalytically dead mutant rescue experiment, loss-of-function/knockdown morphological analysis The Journal of cell biology High 26598618
2016 Neuron-specific deletion of JMJD2B in mice leads to increased total spine number but decreased mature spines in hippocampal CA1 region, hyperactive behavior, working memory deficits, and epileptic-like seizures, establishing a role for KDM4B-mediated H3K9me3 demethylation in CNS development and function. Conditional cre-loxP knockout mice, spine morphology analysis, behavioral testing Translational psychiatry High 27023172
2017 KDM4B/JMJD2B is a p53-inducible gene; p53 directly regulates JMJD2B by binding a canonical p53 consensus motif in the JMJD2B promoter. JMJD2B induction attenuates p53 target gene expression (p21, PIG3, PUMA) in a catalytic-activity-dependent manner. ChIP showing p53 promoter binding, catalytically inactive mutant, siRNA knockdown, xenograft tumor growth Nucleic acids research High 28073943
2017 ERK phosphorylates JMJD2B at Thr305, Ser352, Ser566, and Thr1065 upon glucose deprivation, protecting JMJD2B from ubiquitination and proteasomal degradation. Glucose deprivation increases interaction between JMJD2B and p-ERK. JMJD2B epigenetically upregulates GLUT1 by removing H3K9me3 from its promoter. Co-immunoprecipitation, immunoprecipitation with phospho-site mapping, co-fluorescence, ChIP, siRNA knockdown Oncogene High 28945223
2017 KDM4B directly controls expression of metabolic genes Ppargc1a and Ppara in adipose tissue; adipocyte-specific KDM4B knockout in mice causes obesity with reduced energy expenditure and impaired adaptive thermogenesis. Adipocyte-specific conditional KO mice, ChIP, metabolic phenotyping Proceedings of the National Academy of Sciences of the United States of America High 29844188
2018 SCF-Fbxo22 E3 ubiquitin ligase ubiquitylates KDM4B when KDM4B is complexed with tamoxifen-bound ERα; Fbxo22-mediated KDM4B degradation releases SRC coactivator from ER, determining SERM antagonistic activity in breast cancer. Co-IP, ubiquitination assays, Fbxo22 depletion experiments, live-cell imaging of SRC/KDM4B release The Journal of clinical investigation High 30418174
2018 KDM4B interacts with eIF2α in the cytoplasm in a demethylase activity-dependent manner, resulting in reduced phosphorylation of eIF2α and suppression of the unfolded protein response (UPR) pathway independent of its canonical histone demethylase role. Co-IP demonstrating cytoplasmic KDM4B-eIF2α interaction, catalytic mutant experiments, genetic depletion and small molecule inhibition with UPR pathway readouts The Journal of experimental medicine Medium 30266800
2018 JMJD2B (KDM4B) acts as a co-factor of LXRα; it is recruited to LXR response elements (LXRE) in the promoters of lipogenic genes, removes H3K9me2/3, and interacts with activated LXRα to promote lipogenic gene expression. Co-IP, ChIP, reporter assay with LXRE, adenoviral overexpression in mice International journal of molecular sciences Medium 33167594
2019 KDM4B is phosphorylated by protein kinase A under castration-resistance-promoting conditions; phosphorylated KDM4B binds splicing factor SF3B3, binds RNA near the 5' end of cryptic exon CE3 of androgen receptor pre-mRNA, increases local chromatin accessibility, and couples the spliceosome to chromatin to promote AR-V7 inclusion. Co-IP, RNA binding assays, chromatin accessibility profiling, genome-wide KDM4B RNA binding, splice isoform analysis Nucleic acids research High 31647098
2019 KDM4B physically interacts with c-Jun and is co-recruited to IL-8, MMP1, and ITGAV promoters via its demethylation activity; depletion of KDM4B decreases integrin αV expression and IL-8 production in response to H. pylori infection. Co-IP, ChIP, siRNA knockdown, migration assays Cell death & disease Medium 30683841
2019 KDM4B interacts with TRAF6 and promotes TRAF6-mediated K63-linked ubiquitination of AKT, leading to AKT activation; this promotes glucose uptake by upregulating GLUT1 in colorectal cancer. Co-IP, ubiquitination assays, AKT signaling analysis, glucose uptake assays Journal of experimental & clinical cancer research Medium 31931846
2020 JMJD2B (KDM4B) is induced by EndMT-promoting conditions and controls endothelial-to-mesenchymal transition; it removes H3K9me3 site-specifically at promoters of mesenchymal genes (CNN1) and TGF-β pathway genes (AKT3, SULF1). Endothelial-specific JMJD2B deletion in vivo reduces EndMT after myocardial infarction. ChIP showing site-specific H3K9me3 changes, siRNA knockdown, endothelial-specific conditional KO mice, myocardial infarction model Proceedings of the National Academy of Sciences of the United States of America High 32034099
2021 KDM4B loss in MSCs exacerbates skeletal aging by increasing H3K9me3, impairs MSC self-renewal by inducing senescence-associated heterochromatin foci, and is required for parathyroid hormone-mediated bone anabolism; KDM4B epigenetically coordinates β-catenin/Smad1-mediated transcription by removing H3K9me3. Conditional KO mice, ChIP, senescence assays (SAHF formation), PTH-stimulation experiments Cell stem cell High 33571444
2021 KDM4B inactivation (via H3.3G34R or IDH1/2 mutations) in ATRX-mutated glioblastoma promotes ALT (Alternative Lengthening of Telomeres); KDM4B overexpression in ALT cancer cells abrogates ALT-associated features; KDM4B is identified as the key demethylase inactivated in ALT. Mouse ESC quadruple KO (ATRX/TP53/TERT/KDM4B), ALT assays, KDM4B overexpression in ALT cells Nature communications High 33972520
2021 KDM4B forms a complex with CCAR1 and MED1; the KDM4B-CCAR1-MED1 complex localizes to promoters of osteoclast-related genes upon RANKL stimulation, induces euchromatinization via H3K9 demethylation, and recruits NF-κB p65 via direct interaction between KDM4B and p65. Myeloid-specific KDM4B KO mice show osteopetrosis. Co-IP, genome-wide ChIP-seq, myeloid-specific conditional KO mice, TRAP staining, ovariectomy model Bone research High 34031372
2021 KDM4B physically interacts with c-Myc and is co-recruited with c-Myc to promoters of metabolic genes (LDHA, ENO1, PFK); KDM4B and c-Myc synergistically promote transactivation of LDHA in a demethylase-dependent manner, driving Warburg metabolism in castration-resistant prostate cancer. Co-IP defining interaction region, reporter activity assay, ChIP, Seahorse metabolomics, demethylase-dependent reporter assay Theranostics High 34335964
2021 JMJD2B/KDM4B forms a protein complex with TFAP2C and LSD1 in trophoblast stem cells; this complex predominantly occupies active gene promoters and regulates TSC transcriptional program. KDM4B knockdown causes TSC differentiation and is associated with loss of H3K36me3 on embryonic lineage genes. ChIP-seq, transcriptome analysis, protein complex characterization, shRNA knockdown Scientific reports Medium 33441614
2021 KDM4B silencing in t(8;21) AML disrupts chromatin accessibility at AML1-ETO-binding sites, alters active enhancer marks, and suppresses AML1-ETO-inducible gene expression; methylated-histone binding modules of KDM4B are required for the proliferative effect. Kdm4b conditional KO mice show attenuated AML1-ETO-mediated clonogenic potential and delayed leukemia. shRNA knockdown, ATAC-seq chromatin accessibility, KDM4B mutant rescue (methylated-histone binding modules), conditional KO mice with AML1-ETO leukemia model FASEB bioAdvances High 34938963
2023 HIF1α transcriptionally activates WTAP (m6A methyltransferase complex component) in t(8;21) AML; WTAP enhances m6A methylation on KDM4B transcripts, stabilizing KDM4B mRNA and increasing KDM4B expression. KDM4B knockdown inhibits leukemia cell growth, establishing a crosstalk between m6A RNA methylation and H3K9 histone methylation via KDM4B. m6A-seq, mRNA stability assays, HIF1α ChIP at WTAP promoter, KDM4B knockdown in leukemia cells and mice Leukemia Medium 37087529
2023 KDM4B regulates MYC stability through the E3 ligase complex SCFFBXL3+CRY2, epigenetically activates CCNB1 transcription by removing H3K9me3, and epigenetically activates miR-181d-5p transcription which in turn enhances MYC stability in glioblastoma. Co-IP, ChIP, ubiquitination assays, siRNA knockdown, xenograft models Clinical epigenetics Medium 38093312
2024 UCHL1 deubiquitinase stabilizes KDM4B protein by mediating its deubiquitination; KDM4B is directly bound to the VEGFA promoter, removes H3K9me3, and co-operates with HIF2α to activate VEGFA transcription in clear cell renal cell carcinoma. In vivo ubiquitination assays, UCHL1 C90A catalytic mutant, ChIP at VEGFA promoter, Co-IP, luciferase reporter Translational oncology Medium 38743986
2010 JMJD2B (KDM4B) is regulated by both ERα and HIF-1α; it drives breast cancer cell proliferation in normoxia and hypoxia and epigenetically regulates cell cycle genes such as CCND1, CCNA1, and WEE1. siRNA knockdown, ChIP, proliferation assays under normoxia and hypoxia Cancer research Medium 20682797
2014 KDM4B interacts with MyoD in C2C12 myoblasts, binds to MyoD and myogenin promoters in vivo, and demethylates H3K9me3 at these promoters; KDM4B depletion reduces MyoD and myogenin expression and inhibits myogenic differentiation. Co-IP, ChIP, luciferase reporter, shRNA knockdown, rescue with exogenous MyoD Biochemical and biophysical research communications Medium 25534856
2019 KDM4B demethylates H3K9me3 at RUNX2 promoter in response to IL-6/sIL-6R/STAT3 signaling; STAT3 binds the RUNX2 promoter and recruits JMJD2B to suppress H3K9me3 and activate RUNX2 expression, driving VSMC transformation into osteoblast-like cells. ChIP-PCR at RUNX2 promoter, STAT3 knockdown, JMJD2 inhibitor (JIB04), IL-6/sIL-6R stimulation Bone Medium 30981888

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Jmjd2b antagonizes H3K9 trimethylation at pericentric heterochromatin in mammalian cells. Genes & development 302 16738407
2012 Histone demethylases KDM4B and KDM6B promotes osteogenic differentiation of human MSCs. Cell stem cell 285 22770241
2008 The histone demethylases JMJD1A and JMJD2B are transcriptional targets of hypoxia-inducible factor HIF. The Journal of biological chemistry 282 18984585
2011 Histone demethylase JMJD2B coordinates H3K4/H3K9 methylation and promotes hormonally responsive breast carcinogenesis. Proceedings of the National Academy of Sciences of the United States of America 215 21502505
2011 Histone demethylase JMJD2B functions as a co-factor of estrogen receptor in breast cancer proliferation and mammary gland development. PloS one 157 21445275
2010 The histone demethylase JMJD2B is regulated by estrogen receptor alpha and hypoxia, and is a key mediator of estrogen induced growth. Cancer research 153 20682797
2021 Loss of KDM4B exacerbates bone-fat imbalance and mesenchymal stromal cell exhaustion in skeletal aging. Cell stem cell 139 33571444
2013 Kdm4b histone demethylase is a DNA damage response protein and confers a survival advantage following γ-irradiation. The Journal of biological chemistry 126 23744078
2013 The lysine demethylase, KDM4B, is a key molecule in androgen receptor signalling and turnover. Nucleic acids research 106 23435229
2013 Distinct and combinatorial functions of Jmjd2b/Kdm4b and Jmjd2c/Kdm4c in mouse embryonic stem cell identity. Molecular cell 105 24361252
2020 Enterotoxigenic Bacteroides fragilis induces the stemness in colorectal cancer via upregulating histone demethylase JMJD2B. Gut microbes 95 32684087
2013 JMJD2B promotes epithelial-mesenchymal transition by cooperating with β-catenin and enhances gastric cancer metastasis. Clinical cancer research : an official journal of the American Association for Cancer Research 95 24077348
2019 IL-6 and sIL-6R induces STAT3-dependent differentiation of human VSMCs into osteoblast-like cells through JMJD2B-mediated histone demethylation of RUNX2. Bone 89 30981888
2014 KDM4B as a target for prostate cancer: structural analysis and selective inhibition by a novel inhibitor. Journal of medicinal chemistry 83 24971742
2012 HIF-1α-induced histone demethylase JMJD2B contributes to the malignant phenotype of colorectal cancer cells via an epigenetic mechanism. Carcinogenesis 76 22745382
2013 KDM4B is a master regulator of the estrogen receptor signalling cascade. Nucleic acids research 70 23723241
2011 Histone demethylase JMJD2B is required for tumor cell proliferation and survival and is overexpressed in gastric cancer. Biochemical and biophysical research communications 65 22133676
2011 The histone demethylase JMJD2B plays an essential role in human carcinogenesis through positive regulation of cyclin-dependent kinase 6. Cancer prevention research (Philadelphia, Pa.) 60 21930796
2015 The role of histone demethylase KDM4B in Myc signaling in neuroblastoma. Journal of the National Cancer Institute 59 25925418
2013 p53 promotes repair of heterochromatin DNA by regulating JMJD2b and SUV39H1 expression. Oncogene 57 23376847
2012 Histone demethylase Kdm4b functions as a co-factor of C/EBPβ to promote mitotic clonal expansion during differentiation of 3T3-L1 preadipocytes. Cell death and differentiation 57 22722334
2015 Transforming Growth Factor-β-Induced KDM4B Promotes Chondrogenic Differentiation of Human Mesenchymal Stem Cells. Stem cells (Dayton, Ohio) 55 26485430
2012 Transient JMJD2B-mediated reduction of H3K9me3 levels improves reprogramming of embryonic stem cells into cloned embryos. Molecular and cellular biology 55 23263990
2019 Histone lysine demethylase KDM4B regulates the alternative splicing of the androgen receptor in response to androgen deprivation. Nucleic acids research 54 31647098
2016 The histone demethylase KDM4B regulates peritoneal seeding of ovarian cancer. Oncogene 52 27869162
2018 KDM4B protects against obesity and metabolic dysfunction. Proceedings of the National Academy of Sciences of the United States of America 50 29844188
2020 The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition. Proceedings of the National Academy of Sciences of the United States of America 47 32034099
2018 Fbxo22-mediated KDM4B degradation determines selective estrogen receptor modulator activity in breast cancer. The Journal of clinical investigation 47 30418174
2020 KDM4B facilitates colorectal cancer growth and glucose metabolism by stimulating TRAF6-mediated AKT activation. Journal of experimental & clinical cancer research : CR 45 31931846
2014 Stimulation of β-catenin and colon cancer cell growth by the KDM4B histone demethylase. International journal of oncology 45 24481461
2021 Mutations inhibiting KDM4B drive ALT activation in ATRX-mutated glioblastomas. Nature communications 44 33972520
2019 KDM4B: A Nail for Every Hammer? Genes 44 30759871
2015 miR-491-5p functions as a tumor suppressor by targeting JMJD2B in ERα-positive breast cancer. FEBS letters 44 25725194
2021 Targeting KDM4B that coactivates c-Myc-regulated metabolism to suppress tumor growth in castration-resistant prostate cancer. Theranostics 40 34335964
2018 KDM4B-regulated unfolded protein response as a therapeutic vulnerability in PTEN-deficient breast cancer. The Journal of experimental medicine 37 30266800
2012 Histone demethylase JMJD2B-mediated cell proliferation regulated by hypoxia and radiation in gastric cancer cell. Biochimica et biophysica acta 37 23046878
2011 Triptolide induces cell-cycle arrest and apoptosis of human multiple myeloma cells in vitro via altering expression of histone demethylase LSD1 and JMJD2B. Acta pharmacologica Sinica 36 22120968
2017 KDM4B-mediated epigenetic silencing of miRNA-615-5p augments RAB24 to facilitate malignancy of hepatoma cells. Oncotarget 35 27487123
2017 Role of JMJD2B in colon cancer cell survival under glucose-deprived conditions and the underlying mechanisms. Oncogene 35 28945223
2019 Upregulated KDM4B promotes prostate cancer cell proliferation by activating autophagy. Journal of cellular physiology 34 31468537
2018 Histone Demethylase KDM4B Promotes DNA Damage by Activating Long Interspersed Nuclear Element-1. Cancer research 34 30459150
2007 Comparative integromics on JMJD2A, JMJD2B and JMJD2C: preferential expression of JMJD2C in undifferentiated ES cells. International journal of molecular medicine 34 17611647
2021 MicroRNA-15a Carried by Mesenchymal Stem Cell-Derived Extracellular Vesicles Inhibits the Immune Evasion of Colorectal Cancer Cells by Regulating the KDM4B/HOXC4/PD-L1 Axis. Frontiers in cell and developmental biology 33 33732698
2019 KDM4B is a coactivator of c-Jun and involved in gastric carcinogenesis. Cell death & disease 33 30683841
2018 Histone H3K9 demethylase JMJD2B induces hepatic steatosis through upregulation of PPARγ2. Scientific reports 33 30214048
2017 KDM4B/JMJD2B is a p53 target gene that modulates the amplitude of p53 response after DNA damage. Nucleic acids research 33 28073943
2017 Histone H3K9 Demethylase JMJD2B Activates Adipogenesis by Regulating H3K9 Methylation on PPARγ and C/EBPα during Adipogenesis. PloS one 32 28060835
2017 KDM4B-mediated reduction of H3K9me3 and H3K36me3 levels improves somatic cell reprogramming into pluripotency. Scientific reports 32 28790329
2016 Deletion of JMJD2B in neurons leads to defective spine maturation, hyperactive behavior and memory deficits in mouse. Translational psychiatry 32 27023172
2013 Heat shock protein 90 (Hsp90) selectively regulates the stability of KDM4B/JMJD2B histone demethylase. The Journal of biological chemistry 31 23589305
2020 Histone H3K9 Demethylase JMJD2B Plays a Role in LXRα-Dependent Lipogenesis. International journal of molecular sciences 30 33167594
2016 JMJD2B is required for Helicobacter pylori-induced gastric carcinogenesis via regulating COX-2 expression. Oncotarget 30 27232941
2015 Emodin attenuates radioresistance induced by hypoxia in HepG2 cells via the enhancement of PARP1 cleavage and inhibition of JMJD2B. Oncology reports 29 25607726
2020 Targeting the KDM4B-AR-c-Myc axis promotes sensitivity to androgen receptor-targeted therapy in advanced prostate cancer. The Journal of pathology 28 32617978
2022 The Diverse Roles of Histone Demethylase KDM4B in Normal and Cancer Development and Progression. Frontiers in cell and developmental biology 27 35186950
2018 MiRNA-491-5p inhibits cell proliferation, invasion and migration via targeting JMJD2B and serves as a potential biomarker in gastric cancer. American journal of translational research 27 29511447
2015 KDM4B promotes epithelial-mesenchymal transition through up-regulation of ZEB1 in pancreatic cancer. Acta biochimica et biophysica Sinica 27 26511091
2021 The KDM4B-CCAR1-MED1 axis is a critical regulator of osteoclast differentiation and bone homeostasis. Bone research 26 34031372
2020 JMJD2B-induced amino acid alterations enhance the survival of colorectal cancer cells under glucose-deprivation via autophagy. Theranostics 26 32483417
2018 Distal-less homeobox 5 promotes the osteo-/dentinogenic differentiation potential of stem cells from apical papilla by activating histone demethylase KDM4B through a positive feedback mechanism. Experimental cell research 26 30503866
2015 KDM4A, KDM4B and KDM4C in non-small cell lung cancer. International journal of clinical and experimental pathology 26 26722485
2014 Silencing of JMJD2B induces cell apoptosis via mitochondria-mediated and death receptor-mediated pathway activation in colorectal cancer. Journal of digestive diseases 26 24957706
2017 KDM4B histone demethylase and G9a regulate expression of vascular adhesion proteins in cerebral microvessels. Scientific reports 25 28327608
2016 KDM4B plays an important role in mitochondrial apoptosis by upregulating HAX1 expression in colorectal cancer. Oncotarget 25 27506941
2020 Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects. American journal of human genetics 24 33232677
2018 KDM4B promotes DNA damage response via STAT3 signaling and is a target of CREB in colorectal cancer cells. Molecular and cellular biochemistry 24 29633065
2015 KDM4B and KDM4A promote endometrial cancer progression by regulating androgen receptor, c-myc, and p27kip1. Oncotarget 24 26397136
2018 Hypoxia and Hormone-Mediated Pathways Converge at the Histone Demethylase KDM4B in Cancer. International journal of molecular sciences 23 29342868
2018 Inhibition of the histone demethylase KDM4B leads to activation of KDM1A, attenuates bacterial-induced pro-inflammatory cytokine release, and reduces osteoclastogenesis. Epigenetics 23 29927684
2023 HIF1α-mediated transactivation of WTAP promotes AML cell proliferation via m6A-dependent stabilization of KDM4B mRNA. Leukemia 22 37087529
2018 JMJD2B/KDM4B inactivation in adipose tissues accelerates obesity and systemic metabolic abnormalities. Genes to cells : devoted to molecular & cellular mechanisms 21 30073721
2018 KDM4B promotes gastric cancer metastasis by regulating miR-125b-mediated activation of Wnt signaling. Journal of cellular biochemistry 21 30485532
2017 Heterochromatin Reduction Correlates with the Increase of the KDM4B and KDM6A Demethylases and the Expression of Pericentromeric DNA during the Acquisition of a Transformed Phenotype. Journal of Cancer 21 28928876
2019 The Histone Demethylase Enzymes KDM3A and KDM4B Co-Operatively Regulate Chromatin Transactions of the Estrogen Receptor in Breast Cancer. Cancers 20 31390833
2015 Histone demethylase KDM4B regulates otic vesicle invagination via epigenetic control of Dlx3 expression. The Journal of cell biology 19 26598618
2012 TSA-induced JMJD2B downregulation is associated with cyclin B1-dependent survivin degradation and apoptosis in LNCap cells. Journal of cellular biochemistry 19 22388778
2021 Activation of TC10-Like Transcription by Lysine Demethylase KDM4B in Colorectal Cancer Cells. Frontiers in cell and developmental biology 18 34249900
2014 JMJD2B as a potential diagnostic immunohistochemical marker for hepatocellular carcinoma: a tissue microarray-based study. Acta histochemica 18 25533242
2016 Strong KDM4B and KDM4D Expression Associates with Radioresistance and Aggressive Phenotype in Classical Hodgkin Lymphoma. Anticancer research 17 27630312
2015 Histone demethylase JMJD2B and JMJD2C induce fibroblast growth factor 2: mediated tumorigenesis of osteosarcoma. Medical oncology (Northwood, London, England) 17 25636512
2020 Osmolarity controls the differentiation of adipose-derived stem cells into nucleus pulposus cells via histone demethylase KDM4B. Molecular and cellular biochemistry 16 32594337
2014 The histone demethylase KDM4B interacts with MyoD to regulate myogenic differentiation in C2C12 myoblast cells. Biochemical and biophysical research communications 16 25534856
2012 Functional analysis of histone demethylase Jmjd2b on lipopolysaccharide-treated murine neural stem cells (NSCs). Neurotoxicity research 15 22890720
2020 Inhibition of microRNA-27b-3p relieves osteoarthritis pain via regulation of KDM4B-dependent DLX5. BioFactors (Oxford, England) 14 32856377
2022 Histone H3K9 demethylase JMJD2B/KDM4B promotes osteogenic differentiation of bone marrow-derived mesenchymal stem cells by regulating H3K9me2 on RUNX2. PeerJ 13 36217382
2021 Histone demethylase JMJD2B/KDM4B regulates transcriptional program via distinctive epigenetic targets and protein interactors for the maintenance of trophoblast stem cells. Scientific reports 13 33441614
2024 circBRAF promotes the progression of triple-negative breast cancer through modulating methylation by recruiting KDM4B to histone H3K9me3 and IGF2BP3 to mRNA. American journal of cancer research 12 38859856
2019 The histone demethylase JMJD2B is critical for p53-mediated autophagy and survival in Nutlin-treated cancer cells. The Journal of biological chemistry 12 31036564
2021 Effects of demethylase KDM4B on the biological characteristics and function of yak cumulus cells in vitro. Theriogenology 10 34425304
2024 Super-enhancer-driven LncRNA PPARα-seRNA exacerbates glucolipid metabolism and diabetic cardiomyopathy via recruiting KDM4B. Molecular metabolism 9 38950776
2023 KDM4B down-regulation facilitated breast cancer cell stemness via PHGDH upregulation in H3K36me3-dependent manner. Molecular and cellular biochemistry 9 37249813
2023 KDM4B: A promising oncology therapeutic target. Cancer science 9 37923555
2023 Histone demethylase KDM4B accelerates the progression of glioblastoma via the epigenetic regulation of MYC stability. Clinical epigenetics 9 38093312
2010 Mutant genetic background affects the functional rearrangement and kinetic properties of JMJD2b histone demethylase. Journal of molecular biology 9 21073875
2022 Therapeutic targeting of histone lysine demethylase KDM4B blocks the growth of castration-resistant prostate cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 8 36495660
2021 KDM4B Overexpression Promotes the Growth, Migration, and Invasion of Rheumatoid Arthritis Fibroblast-Like Synoviocytes by Activating STAT3 Pathway. Biochemical genetics 8 33909202
2021 KDM4B promotes acute myeloid leukemia associated with AML1-ETO by regulating chromatin accessibility. FASEB bioAdvances 8 34938963
2024 Deubiquitinase UCHL1 stabilizes KDM4B to augment VEGF signaling and confer bevacizumab resistance in clear cell renal cell carcinoma. Translational oncology 7 38743986
2021 Role for the Histone Demethylase KDM4B in Rhabdomyosarcoma via CDK6 and CCNA2: Compensation by KDM4A and Apoptotic Response of Targeting Both KDM4B and KDM4A. Cancers 7 33917420
2018 Histone demethylase KDM4A and KDM4B expression in granulosa cells from women undergoing in vitro fertilization. Journal of assisted reproduction and genetics 7 29536385