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Showing KDM4A — JMJD2A is a alias.

KDM4A

Lysine-specific demethylase 4A · UniProt O75164

Length
1064 aa
Mass
120.7 kDa
Annotated
2026-06-10
100 papers in source corpus 43 papers cited in narrative 43 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KDM4A (JMJD2A/JHDM3A) is a JmjC-domain, Fe(II)- and 2-oxoglutarate-dependent histone demethylase that removes di- and tri-methyl marks from histone H3K9 and H3K36 (and H1.4K26), and through this catalysis controls chromatin accessibility, replication, and transcriptional programs across development, differentiation, and oncogenesis (PMID:16603238, PMID:16732292, PMID:19144645, PMID:23871696). Crystal structures of its catalytic core (JmjN+JmjC+zinc finger) bound to methylated H3K9 and H3K36 peptides define a lysyl-binding pocket whose main-chain contacts and bent substrate conformations dictate methylation-state and sequence selectivity, including exclusion of H3K27 (PMID:16677698, PMID:17589501, PMID:17567753). By erasing H3K9me3, KDM4A antagonizes HP1-nucleated heterochromatin, and its overexpression accelerates S-phase, alters replication timing, and drives site-specific rereplication and copy-number gain in an enzymatic-activity-dependent manner that is opposed by Suv39h1/HP1γ (PMID:16732292, PMID:21145482, PMID:23871696); KDM4A inhibition conversely stabilizes liquid-like HP1γ puncta, stalls replication forks, and triggers cGAS-STING-dependent antitumor immunity (PMID:33743195). KDM4A is recruited to specific loci by transcription factors and corepressor/coactivator complexes—pRb/HDAC and N-CoR for E2F- and ASCL2-target repression, and AR, E2F1, ETV1, PPARγ (via GPS2), and the PAF1 complex for target activation—linking demethylation to androgen signaling, metabolic gene control, leukemogenesis, and tumorigenesis (PMID:15927959, PMID:16024779, PMID:17555712, PMID:27626669, PMID:26731476, PMID:24953653, PMID:34083515). KDM4A redundantly with KDM4C maintains ESC self-renewal and is required for oocyte zygotic genome activation, myogenesis, and adipo-/osteogenic lineage choice through demethylation of defined target loci (PMID:27266524, PMID:32231309, PMID:34011940, PMID:31515577). Its abundance is tightly controlled by ubiquitin-proteasome turnover via SCF(FbxL4) and SCF(FBXO22) and by RNF8/RNF168, the latter degradation permitting 53BP1 recruitment at DNA damage sites, while USP1 deubiquitination, SUMOylation at K471, and oxygen availability further tune its chromatin occupancy and activity (PMID:22373579, PMID:21757720, PMID:21768309, PMID:28051298, PMID:38727079, PMID:32133742).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2006 High

    Established the founding enzymatic identity—that KDM4A is a histone demethylase—answering whether trimethyl-lysine marks are reversible and defining its H3K9me3/H3K36me3 substrates.

    Evidence In vitro demethylase assays with catalytic-mutant controls, cellular over/knockdown, and C. elegans genetics

    PMID:16603238 PMID:16732292

    Open questions at the time
    • Did not resolve atomic basis of substrate selection
    • In vivo locus-specific targeting not yet mapped
  2. 2006 High

    Connected demethylase activity to chromatin state by showing KDM4A antagonizes HP1 recruitment and de-represses active genes, establishing functional consequences of erasing H3K9me3.

    Evidence Reciprocal siRNA/overexpression with immunofluorescence and RT-PCR readouts

    PMID:16732292

    Open questions at the time
    • Mechanism of locus selection unaddressed
    • Direct HP1 binding vs indirect competition not distinguished here
  3. 2007 High

    Resolved the structural mechanism of methylation-state and sequence selectivity, explaining why KDM4A acts on H3K9 and H3K36 but not H3K27.

    Evidence X-ray co-crystal structures of catalytic core with tri-/di-/monomethyl peptides plus mutagenesis and activity assays

    PMID:16677698 PMID:17567753 PMID:17589501

    Open questions at the time
    • Full-length enzyme/reader-domain architecture not resolved
    • Dynamics of catalysis not captured by static structures
  4. 2005 Medium

    Identified KDM4A as a transcriptional corepressor that engages pRb/HDAC and N-CoR via its tandem Tudor domain, showing it functions beyond bulk demethylation in targeted gene repression.

    Evidence Co-IP, GST pulldown, ChIP, reporter assays, and domain deletion mapping

    PMID:15927959 PMID:16024779

    Open questions at the time
    • Single-lab interactions without independent structural validation
    • Whether repression requires demethylase activity unclear
  5. 2007 Medium

    Linked KDM4A to nuclear-receptor signaling by showing catalytic-activity-dependent coactivation of androgen receptor target genes.

    Evidence Co-IP, domain mapping, catalytic-mutant reporter assays, and siRNA in LNCaP cells

    PMID:17555712

    Open questions at the time
    • Direct histone substrate at AR target promoters not defined here
    • Single-lab evidence
  6. 2008 High

    Defined HP1 as a regulator of KDM4A targeting and activity, showing HP1 binding stimulates H3K36 demethylation at specific heterochromatic genes.

    Evidence AP-MS, in vitro demethylase assays, domain mapping, and ChIP in Drosophila

    PMID:19061644 PMID:22761891

    Open questions at the time
    • Conservation of HP1 stimulation in mammalian KDM4A not fully established
    • Ortholog-based mechanism
  7. 2009 Medium

    Expanded the substrate repertoire to linker histone H1.4K26, showing KDM4A reverses G9a-deposited marks beyond core histones.

    Evidence In vitro methylation/demethylation assays with cellular over/knockdown

    PMID:19144645

    Open questions at the time
    • Physiological consequence of H1.4K26 demethylation not defined
    • Single-lab evidence
  8. 2011 Medium

    Established cell-cycle-coupled proteasomal turnover of KDM4A via SCF(FbxL4) and SCF(FBXO22), linking enzyme abundance to S-phase progression and histone-mark homeostasis.

    Evidence Co-IP, domain mapping, ubiquitin-rescue, BrdU incorporation, and histone-mark westerns

    PMID:21757720 PMID:21768309

    Open questions at the time
    • Degron and signal controlling F-box recognition undefined
    • Single-lab Co-IP-based ligase assignments
  9. 2011 High

    Placed KDM4A in the DNA damage response, showing its tandem Tudor binds H4K20me2 and that RNF8/RNF168-dependent degradation is required to clear KDM4A and permit 53BP1 recruitment.

    Evidence Binding/ubiquitination assays, laser micro-irradiation imaging, and siRNA epistasis

    PMID:22373579

    Open questions at the time
    • Whether demethylase activity contributes to repair distinct from chromatin occlusion unresolved
    • Single lab
  10. 2011 High

    Demonstrated an in vivo developmental/disease role in cardiac hypertrophy, with KDM4A activating FHL1 via H3K9me3 removal in a demethylase-dependent manner.

    Evidence Conditional KO and transgenic mice, ChIP, reporter assays, and catalytic mutant

    PMID:21555854

    Open questions at the time
    • Upstream signals recruiting KDM4A to FHL1 under stress not fully defined
  11. 2012 High

    Showed KDM4A overexpression drives site-specific rereplication and copy-number gain, mechanistically linking demethylase-driven chromatin opening to genomic instability.

    Evidence FISH, BrdU, ChIP, enzymatic mutant, and genetic suppression by Suv39h1/HP1γ

    PMID:23871696

    Open questions at the time
    • How specific amplicon loci are selected unresolved
    • Relevance to spontaneous tumor amplification not directly tested
  12. 2012 Medium

    Connected KDM4A to p53/oncogenic programs, showing interaction with p53 at p21 and repression of CHD5 to suppress Ras-induced senescence.

    Evidence Pulldown, Co-IP, ChIP, senescence and transformation assays

    PMID:22134899 PMID:23168260

    Open questions at the time
    • Direct catalytic mechanism at these loci versus scaffolding unclear
    • Single-lab data
  13. 2016 High

    Reframed KDM4A-p53 interplay as ubiquitin-mediated, showing SCF(Fbxo22)-KDM4A degrades methylated p53 to drive p16 induction and SASP in late senescence.

    Evidence Co-IP, ubiquitination assays, catalytic mutant, and Fbxo22-KO mice

    PMID:26868148

    Open questions at the time
    • How methylation state of p53 is read by the complex not fully resolved
  14. 2016 Medium

    Broadened KDM4A's transcription-factor partnerships and outputs, identifying E2F1, ETV1, and Pol I associations governing metabolism, prostate tumorigenesis, and rDNA transcription.

    Evidence Co-IP, ChIP, metabolic flux/reporter assays, xenografts, and fractionation with kinase inhibition

    PMID:26729372 PMID:26731476 PMID:27626669

    Open questions at the time
    • Whether each axis requires demethylase activity at the implicated promoter not uniformly tested
    • Single-lab studies
  15. 2016 High

    Established essential, partly KDM4C-redundant developmental and leukemic roles, showing requirement for ESC self-renewal and MLL-AF9 AML via Il3ra maintenance.

    Evidence Conditional double/triple-KO mice/ESCs, ChIP-seq, RNA-seq, and genetic rescue

    PMID:27257215 PMID:27266524

    Open questions at the time
    • Degree of paralog redundancy in other tissues not mapped
  16. 2017 Medium

    Defined oxygen sensitivity of KDM4A catalysis, establishing it as an O2-responsive demethylase that can act on the HIF-1α locus to shape the hypoxic response.

    Evidence Kinetic analysis of recombinant enzyme (high KM for O2) plus cellular activity and ChIP under hypoxia

    PMID:28051298 PMID:28894274

    Open questions at the time
    • Quantitative contribution of KDM4A among O2-sensing enzymes in physiological hypoxia unresolved
  17. 2017 Medium

    Identified SUMOylation at K471 as a post-translational switch enhancing KDM4A chromatin association, initially via a KSHV SUMO E3 ligase.

    Evidence In vitro/in vivo SUMOylation assays, K471 mutant, Co-IP, and RNA-seq

    PMID:28212444

    Open questions at the time
    • Endogenous (non-viral) SUMO machinery acting on K471 defined only later
    • Single-lab
  18. 2020 High

    Demonstrated catalytically essential roles in zygotic genome activation and lineage differentiation, showing KDM4A clears H3K9me3 spread over broad H3K4me3 domains and controls myogenic and adipo/osteogenic programs.

    Evidence Conditional KO mice, ChIP-seq, RNA-seq, catalytic mutant, and differentiation assays

    PMID:31515577 PMID:32231309 PMID:34011940

    Open questions at the time
    • Targeting determinants directing KDM4A to broad domains incompletely defined
  19. 2021 Medium

    Revealed therapeutic and ferroptosis-linked consequences of KDM4A loss, showing inhibition stabilizes HP1γ condensates to trigger cGAS-STING immunity and that KDM4A controls SLC7A11 to modulate ferroptosis.

    Evidence Chemical/genetic inhibition, live-cell imaging, DNA fiber and ferroptosis assays, and in vivo immunity readouts

    PMID:33689883 PMID:33743195

    Open questions at the time
    • Single-lab mechanistic chains
    • Direct demethylation versus indirect effects on SLC7A11 not fully separated
  20. 2024 Medium

    Closed the loop on K471 regulation by showing hypoxia-driven endogenous SUMO1 modification enhances chromatin binding and confers ferroptosis resistance via SLC7A11/GPX4.

    Evidence Co-IP, K471 mutagenesis, ChIP, and ferroptosis assays

    PMID:38727079

    Open questions at the time
    • Host SUMO E3 ligase for K471 not identified
    • Single-lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many recruitment cues (transcription factors, HP1, SUMO, oxygen, F-box ligases) are integrated to select specific genomic loci and dictate activation versus repression by a single KDM4A enzyme remains unresolved.
  • No unified model linking PTM state to locus targeting
  • Catalytic versus scaffolding contributions vary by context and are not reconciled
  • Full-length structure with reader domains and partners not determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0016491 oxidoreductase activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0042393 histone binding 2 GO:0140299 molecular sensor activity 1
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 3 GO:0005829 cytosol 2 GO:0005730 nucleolus 1
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1640170 Cell Cycle 3 R-HSA-4839726 Chromatin organization 3 R-HSA-73894 DNA Repair 2
Partners
ARE2F1ETV1FBXO22GPS2HP1 (CBX/HP1Γ)TP53USP1
Complex memberships
N-CoR/HDAC corepressor complexPAF1 complexSCF(FBXO22)SCF(FbxL4)

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 KDM4A (JMJD2A/JHDM3A) demethylates trimethylated histone H3K9 and H3K36 (H3K9me3→H3K9me2; H3K36me3→H3K36me2) in vitro and in cultured cells; catalytically inactive mutant lacks this activity. Overexpression reduces H3K9/K36me3 levels; C. elegans JMJD2A homolog depletion increases H3K9me3 and H3K36me3 and triggers p53-dependent germline apoptosis. In vitro demethylase assay, cell overexpression/RNAi, site-directed mutagenesis, C. elegans genetics Cell High 16603238 16732292
2006 Overexpression of KDM4A (JHDM3A) abrogates HP1 recruitment to heterochromatin, indicating KDM4A antagonizes H3K9me3-nucleated HP1 events. siRNA knockdown of JHDM3A increases H3K9 methylation and upregulates the target gene ASCL2, demonstrating euchromatic demethylation of active-transcription marks. siRNA knockdown, overexpression, immunofluorescence, RT-PCR Nature High 16732292
2006 X-ray crystal structures of the KDM4A catalytic core (JmjN + JmjC + C-terminal domain + zinc finger) with and without α-ketoglutarate and Fe²⁺ defined the substrate-binding pocket; site-directed mutagenesis combined with demethylase activity assays established a molecular model for substrate selection by the JMJD2 family. X-ray crystallography, site-directed mutagenesis, demethylase activity assay Cell High 16677698
2007 Crystal structures of KDM4A bound to tri-, di-, and monomethyl H3K9 and trimethyl H3K36 peptides revealed a lysyl-binding pocket where substrates adopt distinct bent conformations involving the Zn-binding site, providing a structural mechanism for methylation-state selectivity and sequence specificity for H3K9 versus H3K36. X-ray crystallography with peptide substrate co-crystals Nature High 17589501
2007 KDM4A catalytic core complexed with methylated H3K36 peptides (Fe²⁺/N-oxalylglycine) showed that peptide-binding specificity is largely determined by main-chain contacts and primary peptide structure, explaining selectivity for H3K9 and H3K36 but not H3K27; methyl-state selectivity is influenced by space and electrostatic environment in the catalytic center. X-ray crystallography of substrate complexes Proceedings of the National Academy of Sciences of the United States of America High 17567753
2005 KDM4A (JMJD2A) associates in vivo with pRb and class I HDACs (co-immunoprecipitation) and mediates repression of E2F-regulated promoters; the tandem Tudor domain is required for repression of the target gene ASCL2 via the N-CoR complex. Co-immunoprecipitation, reporter gene assay, domain deletion analysis The Journal of biological chemistry Medium 15927959
2005 KDM4A directly interacts with N-CoR through a defined NID (N-CoR interaction domain) both in vitro and in vivo; this interaction is required for JMJD2A-mediated repression of ASCL2 and requires a functional N-CoR complex and the tandem Tudor domain. GST pulldown (in vitro), co-immunoprecipitation (in vivo), chromatin immunoprecipitation, domain deletion mapping Molecular and cellular biology Medium 16024779
2007 KDM4A forms a complex with ligand-bound androgen receptor (AR) through its catalytic domain or C-terminus; overexpression of KDM4A stimulates AR transcriptional activity in a catalytic-activity-dependent manner; knockdown reduces PSA expression in LNCaP cells. Co-immunoprecipitation, reporter assay, domain mapping, siRNA knockdown, RT-PCR Biochemical and biophysical research communications Medium 17555712
2009 G9a/KMT1C methylates histone H1.4K26, and KDM4 family members (including KDM4A) demethylate H1.4K26 in vitro and in vivo, establishing KDM4A as a histone H1.4K26 demethylase. In vitro methylation/demethylation assay, cellular overexpression/knockdown The Journal of biological chemistry Medium 19144645
2008 Drosophila KDM4A (dKDM4A) specifically demethylates H3K36me2 and H3K36me3 in vitro and in vivo; HP1a associates with dKDM4A (chromo shadow domain of HP1a binds HP1-interacting motif of dKDM4A) and stimulates its H3K36 demethylase activity in a manner dependent on the H3K9me-binding motif of HP1a. Affinity purification/mass spectrometry, in vitro demethylase assay, domain mapping, in vivo ChIP/western Molecular cell High 19061644
2010 KDM4A protein levels oscillate in a cell cycle-dependent manner; overexpression increases chromatin accessibility, accelerates S-phase progression, and alters replication timing in an enzymatic-activity-dependent manner. HP1γ overexpression antagonizes these KDM4A-dependent effects, placing KDM4A upstream of HP1γ in controlling chromatin accessibility during DNA replication. Cell cycle synchronization/western blot, FACS, BrdU incorporation, replication timing assay, epistasis via HP1γ overexpression Molecular cell High 21145482
2011 KDM4A (JMJD2A) tandem Tudor domain binds dimethylated histone H4K20 (H4K20me2); KDM4A is ubiquitinated by RNF8 and RNF168 and degraded by the proteasome following DNA damage in an RNF8-dependent manner. This RNF8-dependent degradation is required to allow 53BP1 recruitment to DNA damage sites; ectopic KDM4A expression blocks 53BP1 foci. Co-immunoprecipitation, pulldown, ubiquitination assay, laser-induced DNA damage/immunofluorescence, siRNA epistasis The EMBO journal High 22373579
2011 SCF(FbxL4) ubiquitin ligase complex interacts with KDM4A and targets it for proteasomal degradation; ubiquitin overexpression restores KDM4A turnover and blocks KDM4A-dependent faster S-phase progression in a cullin-1-dependent manner. Co-immunoprecipitation, ubiquitin overexpression rescue, BrdU incorporation, siRNA The Journal of biological chemistry Medium 21757720
2011 SCF(FBXO22) ubiquitin ligase complex targets KDM4A for proteasomal degradation; FBXO22 recognizes KDM4A through its FIST domain binding the JmjN/JmjC catalytic domains. Modulation of FBXO22 levels correspondingly alters histone H3K9 and H3K36 methylation levels and ASCL2 transcription. Co-immunoprecipitation, RNAi, domain mapping, western blot for histone marks, RT-PCR Molecular and cellular biology Medium 21768309
2011 Heart-specific Jmjd2a deletion attenuates hypertrophic response to pressure overload; Jmjd2a transgenic overexpression exacerbates cardiac hypertrophy. KDM4A binds the FHL1 promoter in response to TAC stress, upregulates FHL1 expression via SRF/myocardin, and reduces H3K9me3 at the FHL1 promoter—effects requiring demethylase activity. Conditional knockout/transgenic mouse, ChIP, co-immunoprecipitation, reporter assay, catalytic mutant The Journal of clinical investigation High 21555854
2012 KDM4A (JMJD2A) overexpression leads to site-specific copy number gain (1q12, 1q21, Xq13.1) through rereplication within a single S phase; this requires enzymatic activity and is suppressed by Suv39h1/KMT1A or HP1γ overexpression. Sites with increased copy number show increased KDM4A, MCM, and DNA polymerase occupancy. FISH, BrdU incorporation, ChIP, enzymatic mutant, genetic suppression by Suv39h1/HP1γ overexpression Cell High 23871696
2012 KDM4A interacts with p53 (in vitro and in HCT116 cells) and is co-recruited with p53 to the p21 promoter upon DNA damage. KDM4A knockdown increases p21 and PUMA expression and decreases Bcl-2, inducing apoptosis; the effect is partially p53-dependent. GST pulldown, co-immunoprecipitation, ChIP, siRNA, western blot, flow cytometry Journal of cellular biochemistry Medium 22134899
2012 KDM4A (JMJD2A) promotes cellular transformation by repressing CHD5 (a tumor suppressor regulating p53 activity), thereby inhibiting Ras-induced senescence and collaborating with oncogenic Ras; depletion of KDM4A in K-Ras-expressing A549 cells triggers senescence. Lentiviral overexpression, siRNA, ChIP, senescence assays (SA-β-gal), co-operation with Ras in transformation assay Cell reports Medium 23168260
2013 KDM4A overexpression promotes KSHV reactivation through H3K9me3 demethylase activity; KSHV-encoded K-bZIP protein physically interacts with KDM4A and inhibits its demethylase activity both in vivo and in vitro by blocking substrate accessibility, increasing global H3K9me3. Co-immunoprecipitation, in vitro demethylase inhibition assay, KSHV reactivation/titer assay, catalytic mutant rescue Journal of virology Medium 21228229
2016 SCF(Fbxo22) forms a complex with KDM4A that ubiquitylates methylated p53 for proteasomal degradation; a catalytic mutant of KDM4A stabilizes p53 and enhances its interaction with PHF20. This SCF(Fbxo22)-KDM4A complex is required for p16 induction and SASP during late-phase senescence. Co-immunoprecipitation, ubiquitination assay, catalytic mutant, Fbxo22 knockout mice, western blot Nature communications High 26868148
2015 KDM4A interacts with the translation initiation complex in the cytoplasm (co-immunoprecipitation) and affects distribution of translation initiation factors within polysome fractions; KDM4A depletion reduces protein synthesis and enhances sensitivity to mTOR inhibitors. Co-immunoprecipitation, polysome fractionation, protein synthesis assay (35S-Met), cell viability Cancer discovery Medium 25564516
2016 KDM4A functions as an E2F1 coactivator: it associates with E2F1 on target gene promoters and enhances E2F1 chromatin binding and transcriptional activity. PDK1 and PDK3 are direct KDM4A/E2F1 targets regulating the switch between glycolytic and mitochondrial metabolism; KDM4A depletion elevates pyruvate dehydrogenase activity and ROS. Co-immunoprecipitation, ChIP, reporter assay, metabolic flux assays, siRNA rescue Cell reports Medium 27626669
2016 KDM4A drives prostate tumorigenesis by interacting with ETS transcription factor ETV1; ETV1 recruits KDM4A to the YAP1 promoter, reducing H3K9me3 and increasing YAP1 expression. YAP1 largely rescues growth inhibitory effects of KDM4A depletion, establishing a JMJD2A/ETV1/YAP1 axis. Co-immunoprecipitation, ChIP, mouse xenograft, siRNA, overexpression, rescue experiment The Journal of clinical investigation Medium 26731476
2016 KDM4A associates with RNA Polymerase I at active ribosomal DNA genes and is required for serum-induced activation of rDNA transcription. PI3K/SGK1 signaling controls KDM4A cytoplasmic-to-nuclear localization and thereby its occupancy on rDNA. Co-immunoprecipitation, ChIP, subcellular fractionation, siRNA, reporter assay, kinase inhibition Nature communications Medium 26729372
2014 GPS2/KDM4A pioneering activity is required for promoter-specific recruitment of PPARγ in adipocytes; GPS2 inhibits RNF8 ubiquitin ligase activity, stabilizing KDM4A, which demethylates H3K9 to prime PPARγ-responsive genes including ATGL and HSL. Genome-wide profiling confirms the GPS2/KDM4A requirement for this specific transcriptional program. Co-immunoprecipitation, ChIP-seq, siRNA, ubiquitination assay, lipolysis assay Cell reports Medium 24953653
2017 KDM4A demethylase activity has a high KM(app) for O₂ of ~173 μM (recombinant enzyme), indicating its H3K9me3 demethylase activity responds sensitively to physiological reductions in oxygen concentration; cellular KDM4A activity against H3K9me3 shows a graded response to decreasing O₂ concentrations consistent with biochemical data. Kinetic analysis of recombinant enzyme, immunofluorescence in cells under graded hypoxia ACS chemical biology Medium 28051298
2017 KDM4A demethylates H3K9me3 at the HIF-1α locus; depletion or inactivation of KDM4A causes H3K9me3 accumulation at the HIF-1α gene, reducing HIF-1α mRNA and protein, and decreasing hypoxic transcriptional response, invasion, and migration. ChIP, siRNA, RT-PCR, western blot, invasion/migration assay Scientific reports Medium 28894274
2017 KSHV K-bZIP acts as a viral SUMO-2/3-specific E3 ligase that SUMOylates KDM4A at lysine 471 via a SIM-dependent mechanism; SUMOylation stabilizes KDM4A chromatin association and is required for viral gene transactivation and virion production, as well as for KDM4A-dependent cell proliferation. In vitro and in vivo SUMOylation assay, site-directed mutagenesis (K471), co-immunoprecipitation, RNA-seq, virion production assay PLoS pathogens Medium 28212444
2016 Combined deficiency for Jmjd2a and Jmjd2c (but not individual knockouts) causes early embryonic lethality and impaired ESC self-renewal with spontaneous primitive endoderm differentiation; both demethylases localize to H3K4me3-positive promoters and have redundant roles in preventing H3K9me3 and H3K36me3 accumulation. Catalytic activity is required for ESC maintenance. Conditional triple-KO mouse ESCs, ChIP-seq, RNA-seq, differentiation assays, catalytic mutant rescue The EMBO journal High 27266524
2016 Jmjd2/Kdm4 demethylases are required for MLL-AF9 AML in vivo and in vitro; their activity maintains expression of Il3ra (CD123) by removing H3K9me3 from its promoter. Ectopic Il3ra re-expression rescues AML cell survival in Jmjd2/Kdm4 triple-knockout cells, establishing Il3ra as a critical downstream target. Conditional triple-KO mice, ChIP, lentiviral re-expression rescue, in vivo AML model Genes & development High 27257215
2020 KDM4A-mediated H3K9me3 demethylation at broad H3K4me3 domains in oocytes is essential for normal pre-implantation development and zygotic genome activation; loss of KDM4A causes aberrant H3K9me3 spreading over bdH3K4me3 domains, resulting in insufficient transcriptional activation of genes and endogenous retroviral elements. Catalytic activity of KDM4A is essential for this function. Conditional oocyte KO, ChIP-seq, RNA-seq, catalytic mutant, embryo development assays Nature cell biology High 32231309
2021 KDM4A inhibition promotes formation of liquid-like HP1γ puncta on heterochromatin, stalls DNA replication forks, and activates tumor-cell-intrinsic cGAS-STING signaling through replication-stress-induced cytosolic DNA accumulation, enabling antitumor immunity. KDM4A inhibition (chemical/genetic), live-cell imaging of HP1γ puncta, DNA fiber assay, cGAS-STING pathway assays, CD8+ T cell recruitment assays, in vivo lineage tracing Molecular cell Medium 33743195
2021 KDM4A promotes myogenesis by demethylating H3K9me3 at the MyoD, MyoG, and Myf5 gene loci; conditional KDM4A deletion impairs embryonic and postnatal muscle formation; KDM4A-deficient myoblasts show inhibited differentiation, reduced proliferation, increased p21, and decreased Cyclin D1. Conditional knockout mouse, ChIP, western blot, differentiation assay, satellite cell isolation Cell death & disease Medium 34011940
2021 KDM4A regulates SLC7A11 transcription by demethylating H3K9me3 in the SLC7A11 promoter; KDM4A knockdown increases H3K9me3 at the SLC7A11 promoter, decreases SLC7A11 expression, and promotes ferroptotic cell death in osteosarcoma cells. ChIP assay, siRNA, western blot, ferroptosis assays (iron, MDA, GSH), in vivo xenograft Biochemical and biophysical research communications Medium 33689883
2017 Drosophila KDM4A (dKDM4A) localizes predominantly to heterochromatin and regulates heterochromatin position-effect variegation and organization of repetitive DNA; its enzymatic activity is dispensable for PEV but required for relocation of heterochromatic DSBs outside the domain and for demethylation of H3K56me3 following DNA damage to facilitate repair. Immunofluorescence, PEV assay, FISH, DNA damage assays, enzymatic mutant, Drosophila genetics Developmental cell Medium 28743002
2012 HP1a targets dKDM4A to a subset of heterochromatic genes in Drosophila to regulate H3K36me3 levels; HP1a binding is required for dKDM4A-mediated H3K36me3 demethylation specifically at this gene subset, shown by ChIP-chip in wild-type vs. dkdm4a mutant embryos. ChIP-chip, dkdm4a mutant embryos, genetic epistasis with HP1a PloS one Medium 22761891
2019 KDM4A promotes adipogenic and inhibits osteogenic differentiation by directly binding the promoters of Sfrp4 and C/ebpα, removing H3K9me3, and reducing DNA methylation; overexpression inactivates canonical Wnt signaling via Sfrp4 upregulation. Silencing Sfrp4 rescues the osteogenesis block, placing Sfrp4 downstream of KDM4A in this pathway. ChIP, overexpression/knockdown, catalytic mutant, siRNA rescue, differentiation assays Cellular and molecular life sciences : CMLS Medium 31515577
2020 KDM4A depletion leads to global H3K9me3 and H3K27me3 accumulation at KDM4A-targeted loci in AML cells and downregulates a KDM4A-PAF1-controlled transcriptional program essential for leukemogenesis; KDM4A interacts with the PAF1 complex (distinct from KDM4C-dependent targets). ChIP-seq, RNA-seq, siRNA/shRNA, co-immunoprecipitation, apoptosis assay Cell death & disease Medium 34083515
2020 QM/MM computational analysis shows KDM4A catalysis generates a reactive Fe(IV)-oxo intermediate; substrate binding mode, correlated protein-histone motions, and molecular orbital control synergistically determine reactivity. K241A substitution (consistent with experimental studies) abolishes activity by altering substrate orientation; Ser288 and Thr289 contribute through correlated motions. Molecular dynamics + QM/MM calculations with in silico mutagenesis validated against experimental activity data Chemical science Low 34094257
2024 Hypoxia-like conditions promote SUMO1 modification of KDM4A at lysine K471 (K471 is the primary SUMOylation site, confirmed by mutation), which enhances KDM4A chromatin association, reduces H3K9me3 at the SLC7A11 promoter, and upregulates SLC7A11/GPX4 to confer ferroptosis resistance in cervical cancer cells. Co-immunoprecipitation, site-directed mutagenesis (K471), ChIP, western blot, ferroptosis assays Environmental toxicology Medium 38727079
2016 KDM4A inhibition (KDM4A-silencing or compound C-4) induces TRAIL and DR5 expression by switching promoter-bound histone-modifying complexes: dissociating KDM4A and NCoR-HDAC complex and recruiting histone acetylase CBP at the CHOP gene promoter, thereby de-repressing TRAIL and DR5 transcription. ChIP, siRNA, small-molecule inhibitor, co-immunoprecipitation, apoptosis assay Cell death and differentiation Medium 27612013
2018 KDM4A and KDM4C co-occupy promoters with NF-κB p65 (ChIP-seq/motif analysis) and co-target Wdr5, a MLL complex member; their depletion in B cells potentiates activation and upregulates cell cycle inhibitors Cdkn2c and Cdkn3 via WDR5-dependent H3K4 methylation. ChIP-seq, de novo motif analysis, siRNA, co-immunoprecipitation, B cell activation assay Nucleic acids research Medium 29718303
2019 USP1 is a deubiquitinase that regulates KDM4A K48-linked deubiquitination and protein stability; USP1 inhibition reduces KDM4A levels and suppresses c-Myc expression (a downstream effector of the USP1-KDM4A/androgen receptor axis) in prostate cancer cells. Co-immunoprecipitation, ubiquitination assay, siRNA, western blot, proliferation assay Cancer science Medium 32133742

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 818 16603238
2006 The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36. Nature 499 16732292
2013 KDM4/JMJD2 histone demethylases: epigenetic regulators in cancer cells. Cancer research 360 23644528
2006 Structural insights into histone demethylation by JMJD2 family members. Cell 307 16677698
2012 RNF8- and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1 recruitment to DNA damage sites. The EMBO journal 296 22373579
2007 Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity. Nature 270 17589501
2007 Activation of androgen receptor by histone demethylases JMJD2A and JMJD2D. Biochemical and biophysical research communications 183 17555712
2013 KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors. Cell 179 23871696
2011 Role of androgen receptor and associated lysine-demethylase coregulators, LSD1 and JMJD2A, in localized and advanced human bladder cancer. Molecular carcinogenesis 175 21400613
2011 The histone trimethyllysine demethylase JMJD2A promotes cardiac hypertrophy in response to hypertrophic stimuli in mice. The Journal of clinical investigation 173 21555854
2009 Dynamic Histone H1 Isotype 4 Methylation and Demethylation by Histone Lysine Methyltransferase G9a/KMT1C and the Jumonji Domain-containing JMJD2/KDM4 Proteins. The Journal of biological chemistry 164 19144645
2010 Conserved antagonism between JMJD2A/KDM4A and HP1γ during cell cycle progression. Molecular cell 130 21145482
2006 Diversity within the JMJD2 histone demethylase family. Biochemical and biophysical research communications 120 17207460
2007 Structural basis of the recognition of a methylated histone tail by JMJD2A. Proceedings of the National Academy of Sciences of the United States of America 119 17567753
2005 Functional characterization of JMJD2A, a histone deacetylase- and retinoblastoma-binding protein. The Journal of biological chemistry 109 15927959
2012 Oncogenic features of the JMJD2A histone demethylase in breast cancer. International journal of oncology 107 22948256
2005 JMJD2A is a novel N-CoR-interacting protein and is involved in repression of the human transcription factor achaete scute-like homologue 2 (ASCL2/Hash2). Molecular and cellular biology 105 16024779
2010 Histone demethylase JmjD2A regulates neural crest specification. Developmental cell 104 20833367
2004 Identification and characterization of JMJD2 family genes in silico. International journal of oncology 101 15138608
2012 JMJD2A promotes cellular transformation by blocking cellular senescence through transcriptional repression of the tumor suppressor CHD5. Cell reports 100 23168260
2016 Continual removal of H3K9 promoter methylation by Jmjd2 demethylases is vital for ESC self-renewal and early development. The EMBO journal 98 27266524
2013 Targeting the JMJD2 histone demethylases to epigenetically control herpesvirus infection and reactivation from latency. Science translational medicine 98 23303604
2012 The JMJD2A demethylase regulates apoptosis and proliferation in colon cancer cells. Journal of cellular biochemistry 98 22134899
2016 SCF(Fbxo22)-KDM4A targets methylated p53 for degradation and regulates senescence. Nature communications 97 26868148
2020 KDM4A regulates the maternal-to-zygotic transition by protecting broad H3K4me3 domains from H3K9me3 invasion in oocytes. Nature cell biology 95 32231309
2016 Histone demethylase JMJD2A drives prostate tumorigenesis through transcription factor ETV1. The Journal of clinical investigation 91 26731476
2021 KDM4A-mediated histone demethylation of SLC7A11 inhibits cell ferroptosis in osteosarcoma. Biochemical and biophysical research communications 87 33689883
2011 SCF(FBXO22) regulates histone H3 lysine 9 and 36 methylation levels by targeting histone demethylase KDM4A for ubiquitin-mediated proteasomal degradation. Molecular and cellular biology 85 21768309
2008 Heterochromatin protein 1a stimulates histone H3 lysine 36 demethylation by the Drosophila KDM4A demethylase. Molecular cell 85 19061644
2021 Targeting KDM4A epigenetically activates tumor-cell-intrinsic immunity by inducing DNA replication stress. Molecular cell 79 33743195
2016 8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors. Journal of medicinal chemistry 79 26741168
2017 The Activity of JmjC Histone Lysine Demethylase KDM4A is Highly Sensitive to Oxygen Concentrations. ACS chemical biology 74 28051298
2014 The role of the histone demethylase KDM4A in cancer. Cancer genetics 72 25633974
2016 KDM4A Coactivates E2F1 to Regulate the PDK-Dependent Metabolic Switch between Mitochondrial Oxidation and Glycolysis. Cell reports 71 27626669
2015 KDM4/JMJD2 Histone Demethylase Inhibitors Block Prostate Tumor Growth by Suppressing the Expression of AR and BMYB-Regulated Genes. Chemistry & biology 68 26364928
2016 Jmjd2/Kdm4 demethylases are required for expression of Il3ra and survival of acute myeloid leukemia cells. Genes & development 65 27257215
2012 The oncogenic potential of Jumonji D2 (JMJD2/KDM4) histone demethylase overexpression. Biochemistry and cell biology = Biochimie et biologie cellulaire 65 24219278
2013 Deregulation of the histone demethylase JMJD2A is involved in human carcinogenesis through regulation of the G(1)/S transition. Cancer letters 62 23603248
2015 Lysine demethylase KDM4A associates with translation machinery and regulates protein synthesis. Cancer discovery 60 25564516
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
2019 The KDM4/JMJD2 histone demethylases are required for hematopoietic stem cell maintenance. Blood 59 31434704
2011 A new isoform of the histone demethylase JMJD2A/KDM4A is required for skeletal muscle differentiation. PLoS genetics 57 21694756
2011 The SKP1-Cul1-F-box and leucine-rich repeat protein 4 (SCF-FbxL4) ubiquitin ligase regulates lysine demethylase 4A (KDM4A)/Jumonji domain-containing 2A (JMJD2A) protein. The Journal of biological chemistry 56 21757720
2014 JMJD2A contributes to breast cancer progression through transcriptional repression of the tumor suppressor ARHI. Breast cancer research : BCR 54 24886710
2021 HIF-1α-activated long non-coding RNA KDM4A-AS1 promotes hepatocellular carcinoma progression via the miR-411-5p/KPNA2/AKT pathway. Cell death & disease 50 34903711
2014 Gene-specific methylation control of H3K9 and H3K36 on neurotrophic BDNF versus astroglial GFAP genes by KDM4A/C regulates neural stem cell differentiation. Journal of molecular biology 50 24747049
2019 Histone demethylase KDM4A regulates adipogenic and osteogenic differentiation via epigenetic regulation of C/EBPα and canonical Wnt signaling. Cellular and molecular life sciences : CMLS 48 31515577
2022 Hypoxia Enhances HIF1α Transcription Activity by Upregulating KDM4A and Mediating H3K9me3, Thus Inducing Ferroptosis Resistance in Cervical Cancer Cells. Stem cells international 47 35287356
2014 GPS2/KDM4A pioneering activity regulates promoter-specific recruitment of PPARγ. Cell reports 47 24953653
2011 Histone demethylase JMJD2A regulates Kaposi's sarcoma-associated herpesvirus replication and is targeted by a viral transcriptional factor. Journal of virology 46 21228229
2017 KDM4A regulates HIF-1 levels through H3K9me3. Scientific reports 45 28894274
2015 Histone Demethylases KDM4A and KDM4C Regulate Differentiation of Embryonic Stem Cells to Endothelial Cells. Stem cell reports 45 26120059
2011 Effects of RNA interference-mediated gene silencing of JMJD2A on human breast cancer cell line MDA-MB-231 in vitro. Journal of experimental & clinical cancer research : CR 44 21962223
2020 Fisetin inhibits proliferation of pancreatic adenocarcinoma by inducing DNA damage via RFXAP/KDM4A-dependent histone H3K36 demethylation. Cell death & disease 43 33093461
2017 Vitamin C enhances the expression of IL17 in a Jmjd2-dependent manner. BMB reports 43 27931518
2015 SIRT2 suppresses non-small cell lung cancer growth by targeting JMJD2A. Biological chemistry 42 25719312
2010 The histone demethylase Dmel\Kdm4A controls genes required for life span and male-specific sex determination in Drosophila. Gene 42 19786080
2020 Catalysis by the JmjC histone demethylase KDM4A integrates substrate dynamics, correlated motions and molecular orbital control. Chemical science 39 34094257
2017 Drosophila Histone Demethylase KDM4A Has Enzymatic and Non-enzymatic Roles in Controlling Heterochromatin Integrity. Developmental cell 38 28743002
2016 The histone demethylase JMJD2A/KDM4A links ribosomal RNA transcription to nutrients and growth factors availability. Nature communications 38 26729372
2018 The KDM4A/KDM4C/NF-κB and WDR5 epigenetic cascade regulates the activation of B cells. Nucleic acids research 37 29718303
2016 Efficient therapeutic delivery by a novel cell-permeant peptide derived from KDM4A protein for antitumor and antifibrosis. Oncotarget 37 27081693
2021 KDM4A regulates myogenesis by demethylating H3K9me3 of myogenic regulatory factors. Cell death & disease 36 34011940
2020 Targeting USP1-dependent KDM4A protein stability as a potential prostate cancer therapy. Cancer science 36 32133742
2016 ETS transcription factor ERG cooperates with histone demethylase KDM4A. Oncology reports 35 27109047
2014 JMJD2A-dependent silencing of Sp1 in advanced breast cancer promotes metastasis by downregulation of DIRAS3. Breast cancer research and treatment 35 25193278
2016 Identification and characterization of PKF118-310 as a KDM4A inhibitor. Epigenetics 34 27767379
2007 Comparative integromics on JMJD2A, JMJD2B and JMJD2C: preferential expression of JMJD2C in undifferentiated ES cells. International journal of molecular medicine 34 17611647
2015 The requirement of histone modification by PRDM12 and Kdm4a for the development of pre-placodal ectoderm and neural crest in Xenopus. Developmental biology 33 25576027
2019 JMJD2 promotes acquired cisplatin resistance in non-small cell lung carcinoma cells. Oncogene 32 30967636
2021 Mechanistic insights into KDM4A driven genomic instability. Biochemical Society transactions 30 33492339
2020 RFX5 promotes the progression of hepatocellular carcinoma through transcriptional activation of KDM4A. Scientific reports 30 32883983
2019 Circ_SPECC1 enhances the inhibition of miR-526b on downstream KDM4A/YAP1 pathway to regulate the growth and invasion of gastric cancer cells. Biochemical and biophysical research communications 30 31349968
2017 JMJD2A promotes the Warburg effect and nasopharyngeal carcinoma progression by transactivating LDHA expression. BMC cancer 30 28693517
2017 Identification of the histone lysine demethylase KDM4A/JMJD2A as a novel epigenetic target in M1 macrophage polarization induced by oxidized LDL. Oncotarget 30 29383092
2016 Silencing the epigenetic silencer KDM4A for TRAIL and DR5 simultaneous induction and antitumor therapy. Cell death and differentiation 30 27612013
2018 The Histone Demethylase JMJD2A Modulates the Induction of Hypertrophy Markers in iPSC-Derived Cardiomyocytes. Frontiers in genetics 29 29479368
2017 SUMO modification of a heterochromatin histone demethylase JMJD2A enables viral gene transactivation and viral replication. PLoS pathogens 29 28212444
2017 Maternal expression of the histone demethylase Kdm4a is crucial for pre-implantation development. Development (Cambridge, England) 29 28827393
2021 A KDM4A-PAF1-mediated epigenomic network is essential for acute myeloid leukemia cell self-renewal and survival. Cell death & disease 28 34083515
2019 Improvement in the in vitro development of cloned pig embryos after kdm4a overexpression and an H3K9me3 methyltransferase inhibitor treatment. Theriogenology 28 31791612
2016 Histone Lysine Demethylases of JMJD2 or KDM4 Family are Important Epigenetic Regulators in Reward Circuitry in the Etiopathology of Depression. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 28 27711046
2015 Tetrazolylhydrazides as Selective Fragment-Like Inhibitors of the JumonjiC-Domain-Containing Histone Demethylase KDM4A. ChemMedChem 27 26337137
2018 MiR-10a functions as a tumor suppressor in prostate cancer via targeting KDM4A. Journal of cellular biochemistry 26 30302800
2015 KDM4A, KDM4B and KDM4C in non-small cell lung cancer. International journal of clinical and experimental pathology 26 26722485
2021 Histone demethylase KDM4A plays an oncogenic role in nasopharyngeal carcinoma by promoting cell migration and invasion. Experimental & molecular medicine 25 34385569
2015 KDM4B and KDM4A promote endometrial cancer progression by regulating androgen receptor, c-myc, and p27kip1. Oncotarget 25 26397136
2023 Long noncoding RNAs with peptide-encoding potential identified in esophageal squamous cell carcinoma: KDM4A-AS1-encoded peptide weakens cancer cell viability and migratory capacity. Molecular oncology 24 36965032
2021 Targeting KDM4A-AS1 represses AR/AR-Vs deubiquitination and enhances enzalutamide response in CRPC. Oncogene 24 34759344
2019 JMJD2A sensitizes gastric cancer to chemotherapy by cooperating with CCDC8. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 24 31677131
2016 Downregulation of KDM4A Suppresses the Survival of Glioma Cells by Promoting Autophagy. Journal of molecular neuroscience : MN 24 27514525
2015 A coding single-nucleotide polymorphism in lysine demethylase KDM4A associates with increased sensitivity to mTOR inhibitors. Cancer discovery 24 25564517
2015 IOX1, a JMJD2A inhibitor, suppresses the proliferation and migration of vascular smooth muscle cells induced by angiotensin II by regulating the expression of cell cycle-related proteins. International journal of molecular medicine 24 26530537
2012 Gene regulation by the lysine demethylase KDM4A in Drosophila. Developmental biology 24 23195220
2011 Molecular recognition of H3/H4 histone tails by the tudor domains of JMJD2A: a comparative molecular dynamics simulations study. PloS one 24 21464980
2025 Isoorientin Ameliorates Macrophage Pyroptosis and Atherogenesis by Reducing KDM4A Levels and Promoting SKP1-Cullin1-F-box E3 Ligase-mediated NLRP3 Ubiquitination. Inflammation 23 40133580
2018 miR‑150 promotes the proliferation and migration of non‑small cell lung cancer cells by regulating the SIRT2/JMJD2A signaling pathway. Oncology reports 23 29901178
2020 RETRACTED: KDM4A promotes the growth of non-small cell lung cancer by mediating the expression of Myc via DLX5 through the Wnt/β-catenin signaling pathway. Life sciences 22 33002480
2012 HP1a targets the Drosophila KDM4A demethylase to a subset of heterochromatic genes to regulate H3K36me3 levels. PloS one 22 22761891
2024 Functional mechanism of hypoxia-like conditions mediating resistance to ferroptosis in cervical cancer cells by regulating KDM4A SUMOylation and the SLC7A11/GPX4 pathway. Environmental toxicology 20 38727079

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