Affinage

EZH2

Histone-lysine N-methyltransferase EZH2 · UniProt Q15910

Round 2 corrected
Length
746 aa
Mass
85.4 kDa
Annotated
2026-04-28
130 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EZH2 is the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), where it trimethylates histone H3 at lysine 27 (H3K27me3) through its SET domain to silence developmental regulators, tumor suppressors, and senescence-associated loci such as INK4A-ARF (PMID:12351676, PMID:17344414). Beyond canonical H3K27 methylation, EZH2 recruits DNA methyltransferases to reinforce silencing (PMID:16357870), methylates non-histone substrates including PLZF, SMAD3, and FOXA1 to regulate NKT cell fate, TGFβ signaling, and DNA damage repair (PMID:28223321, PMID:35085106, PMID:35031563), and — upon phosphorylation — switches from a PRC2-dependent repressor to a transcriptional coactivator that partners with androgen receptor, p300, or cMyc independently of H3K27me3 (PMID:23239736, PMID:32631994, PMID:36747009). EZH2 stability is regulated by O-GlcNAcylation at S75, PRMT1-mediated arginine methylation at R342, and USP7-mediated deubiquitination (PMID:24474760, PMID:32895488, PMID:32453339); gain-of-function mutations at Y641 drive H3K27me3 hypermethylation in follicular lymphoma and diffuse large B-cell lymphoma, while loss-of-function mutations confer a tumor-suppressive deficit in myeloid malignancies (PMID:20081860, PMID:20601953).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 2002 High

    Establishing EZH2 as the enzymatic engine of PRC2 resolved the long-standing question of which Polycomb group protein catalyzes histone methylation: EZH2 within the EED-SUZ12-RbAp46/48 complex methylates H3K27 via its SET domain, and this mark recruits PRC1 to enforce gene silencing.

    Evidence Biochemical reconstitution of PRC2 histone methyltransferase activity on nucleosomes, SET-domain mutagenesis, ChIP at Polycomb response elements

    PMID:12351676 PMID:12435631

    Open questions at the time
    • Relative contributions of H3K9 versus H3K27 methylation by PRC2 were initially ambiguous
    • Mechanism of allosteric activation by cofactors EED and SUZ12 unresolved
    • Structural basis for substrate recognition not yet determined
  2. 2002 High

    Linking EZH2 overexpression to prostate cancer proliferation and transcriptional repression established the gene's oncogenic relevance and showed that repression requires both an intact SET domain and HDAC activity.

    Evidence Expression profiling of metastatic prostate cancer, siRNA knockdown, ectopic overexpression with SET-domain mutants, HDAC inhibitor treatment

    PMID:12374981 PMID:14500907

    Open questions at the time
    • Which specific HDACs cooperate with EZH2 was not identified
    • Whether EZH2 oncogenic effects are solely H3K27me3-dependent remained unclear
  3. 2003 High

    Demonstrating that the pRB-E2F pathway controls EZH2 transcription placed PRC2 activity downstream of the cell-cycle machinery, explaining why EZH2 is upregulated in proliferating and transformed cells.

    Evidence pRB/E2F pathway perturbation, RNAi, BrdU incorporation in primary cells

    PMID:14532106

    Open questions at the time
    • Whether other cell-cycle regulators converge on EZH2 transcription was not addressed
    • Post-transcriptional regulation of EZH2 not explored
  4. 2004 High

    Genetic ablation of Suz12 in mice proved that PRC2 integrity is essential for EZH2 catalytic competence in vivo, demonstrating that EZH2 cannot methylate H3K27 as a standalone enzyme.

    Evidence Suz12 conditional knockout embryos with loss of H3K27me2/3, in vitro HMT assay of Suz12-deficient lysates

    PMID:15385962

    Open questions at the time
    • Whether EZH2 retains any non-histone activity without SUZ12 was untested
    • Role of accessory subunits (JARID2, AEBP2) not yet defined
  5. 2005 High

    Discovery that EZH2 directly recruits DNMT1/3A/3B to target promoters revealed a mechanistic bridge between histone methylation and DNA methylation, showing that PRC2-mediated H3K27me3 instructs de novo CpG methylation for stable silencing.

    Evidence Co-immunoprecipitation of EZH2 with DNMTs, bisulfite sequencing of EZH2 target promoters, EZH2 knockdown abolishing DNMT occupancy

    PMID:16357870

    Open questions at the time
    • Whether the EZH2-DNMT interaction is direct or mediated by H3K27me3 was not fully resolved
    • Genome-wide scope of EZH2-directed DNA methylation unknown
  6. 2007 High

    Showing that PRC2-EZH2 occupies and maintains H3K27me3 at the INK4A-ARF locus, with senescence-associated EZH2 downregulation causing PRC1 displacement and p16/p14 derepression, established a direct epigenetic mechanism for the senescence barrier.

    Evidence ChIP for PRC2/H3K27me3/BMI1 during replicative senescence, siRNA knockdown of EZH2

    PMID:17344414

    Open questions at the time
    • Whether senescence-induced EZH2 loss is transcriptional or post-translational was not resolved
    • Contribution of EZH1 compensation at this locus not tested
  7. 2008 High

    Identification of EZH1 as a partially redundant H3K27 methyltransferase that also compacts chromatin independently of catalytic activity revealed two mechanistically distinct PRC2 complexes and explained residual H3K27me3 in Ezh2-null cells.

    Evidence Biochemical purification of PRC2-EZH1, Ezh2-knockout ESCs, double depletion, electron microscopy of chromatin compaction

    PMID:19026780 PMID:19026781

    Open questions at the time
    • Context-specific switching between EZH1 and EZH2 complexes poorly understood
    • Whether EZH1 also has non-histone substrates unknown
  8. 2010 High

    Discovery of recurrent Y641 gain-of-function mutations in lymphoma (enhanced H3K27 trimethylation) alongside loss-of-function mutations in myeloid malignancies revealed that EZH2 acts as both an oncogene and a tumor suppressor depending on lineage context.

    Evidence Targeted sequencing of lymphoma and MDS/MPN cohorts, in vitro HMT assays with mutant enzymes

    PMID:20081860 PMID:20601953

    Open questions at the time
    • How wild-type EZH2 cooperates with Y641 mutant in heterozygous tumors was not fully defined
    • Therapeutic window for EZH2 inhibitors across lineages unresolved
  9. 2010 High

    Demonstration that HOTAIR lncRNA simultaneously scaffolds PRC2 (via EZH2) and LSD1/CoREST established the principle of RNA-mediated coordinate histone modification, linking H3K27 methylation and H3K4 demethylation at shared targets.

    Evidence RNA pulldown, domain deletion mapping, RIP, ChIP, in vitro complex reconstitution

    PMID:20616235

    Open questions at the time
    • Generalizability of lncRNA scaffolding to other PRC2 genomic targets unclear
    • Stoichiometry of the RNA-bridged complex not determined
  10. 2012 High

    The paradigm-shifting finding that phosphorylated EZH2 functions as a transcriptional coactivator for androgen receptor in castration-resistant prostate cancer — independent of PRC2 repression — established a non-canonical, context-dependent activating role for EZH2.

    Evidence ChIP-seq separating EZH2 activating versus repressive sites, phosphorylation-mimetic mutants, co-immunoprecipitation with AR, transcriptome profiling

    PMID:23239736

    Open questions at the time
    • Precise kinase(s) responsible for the activating phosphorylation in CRPC not fully defined at this stage
    • Structural basis for the PRC2-independent interaction unknown
  11. 2014 High

    Identification of O-GlcNAcylation at EZH2 S75 by OGT as a stabilizing modification connected nutrient-sensing signaling to PRC2 chromatin regulation, explaining how metabolic cues modulate H3K27me3 levels.

    Evidence OGT knockdown, S75A mutagenesis, co-immunoprecipitation, ChIP for H3K27me3

    PMID:24474760

    Open questions at the time
    • Whether OGT-mediated stabilization is cell-type specific not tested
    • Interplay with other EZH2 PTMs at this stage incompletely mapped
  12. 2016 High

    EZH2's ability to cleave B2 SINE RNA upon heat stress — activating Pol II elongation independently of methyltransferase activity — expanded EZH2's functional repertoire beyond epigenetic modification to include direct RNA processing.

    Evidence RNA-protein interaction assays, RNase cleavage reconstitution, Pol II ChIP, nuclear run-on in EZH2-depleted and reconstituted cells

    PMID:27984727

    Open questions at the time
    • Whether this RNA-cleavage function operates at non-stress conditions unknown
    • Catalytic residues mediating RNA cleavage not identified
  13. 2017 High

    Direct methylation of the non-histone substrate PLZF by EZH2 — promoting its ubiquitination and degradation independently of PRC2 — established a chromatin-independent role for EZH2 in controlling NKT cell lineage commitment.

    Evidence T-cell-specific Ezh2/Suz12/Eed conditional knockouts, in vitro methyltransferase assay on PLZF, ubiquitination assay, flow cytometry

    PMID:28223321

    Open questions at the time
    • Whether other immune cell lineages are similarly affected by EZH2 non-histone methylation not addressed
    • Structural basis for PLZF recognition by EZH2 unknown
  14. 2018 High

    Myeloid-specific Ezh2 deletion revealed that EZH2 sustains innate immune activation by repressing SOCS3 via H3K27me3, thereby preventing SOCS3-mediated TRAF6 degradation and preserving NF-κB signaling downstream of TLRs.

    Evidence Conditional knockout, ChIP at SOCS3 locus, SOCS3 silencing rescue, colitis and EAE disease models

    PMID:29626115

    Open questions at the time
    • Whether EZH2's macrophage role involves non-histone substrates not explored
    • Applicability to human myeloid biology not directly demonstrated
  15. 2019 High

    Demonstration that EZH2 loss cooperates with oncogenic NRAS to drive myeloid leukemia through BCAT1 derepression and mTOR hyperactivation identified a metabolic vulnerability specific to EZH2-mutant cancers.

    Evidence Conditional EZH2 knockout plus NRASG12D mouse model, ChIP, metabolomics, BCAT1 pharmacologic and genetic inhibition

    PMID:31189531

    Open questions at the time
    • Whether BCAT1-mTOR axis is relevant in human EZH2-mutant MDS/MPN not demonstrated
    • Additional PRC2 target genes contributing to leukemogenesis not surveyed
  16. 2020 High

    Structural and functional characterization of EZH2's partially disordered transactivation domain (TAD) and the role of Src-mediated Y696 phosphorylation in switching EZH2 from histone binding to RNA Pol II binding provided a molecular explanation for its dual repressor/activator identity.

    Evidence Crystal structure of EZH2-EED, NMR of TAD disorder, phosphomimetic mutants, Co-IP with p300 and RNA Pol II, ChIP

    PMID:32461334 PMID:32631994

    Open questions at the time
    • Full-length PRC2-independent EZH2 structure not available
    • How multiple phosphorylation events are coordinated in vivo remains unclear
  17. 2020 High

    Defining the PRMT1-EZH2 R342 methylation axis that blocks CDK1-mediated phosphorylation and subsequent TRAF6 ubiquitination revealed a hierarchical PTM crosstalk mechanism governing EZH2 protein stability.

    Evidence In vitro methylation assay, site-directed mutagenesis (R342), CDK1 kinase assay, ubiquitination assay, mass spectrometry

    PMID:32895488

    Open questions at the time
    • Whether PRMT1-EZH2 crosstalk is altered in cancer contexts not tested
    • Other arginine methylation sites on EZH2 not explored
  18. 2020 Medium

    Two independent studies showing that USP7 deubiquitinates and stabilizes EZH2 identified a druggable node for indirect EZH2 depletion.

    Evidence Co-immunoprecipitation, ubiquitination assays, catalytic-dead USP7 mutant, rescue experiments, xenograft models

    PMID:32064169 PMID:32453339

    Open questions at the time
    • Specificity of USP7 for EZH2 versus other PRC2 subunits unclear
    • No structural data on the USP7-EZH2 interface
  19. 2021 High

    Cryo-EM structures of nucleosome-bound PRC2-EZH1/2 revealed the conformational changes upon substrate engagement and identified a divergent loop essential for nucleosome recognition, methylation, and chromatin compaction.

    Evidence Cryo-EM, divergent loop mutagenesis, in vitro HMT and compaction assays

    PMID:33514705

    Open questions at the time
    • Equivalent high-resolution structure of PRC2-EZH2 on dinucleosomes not available
    • How allosteric stimulation by H3K27me3-EED propagates structurally not fully captured
  20. 2021 High

    Discovery that EZH2 maintains H3K27 acetylation (not methylation) at the Neat1 promoter via its SANT2 domain to enable p65-driven inflammasome gene activation added yet another non-canonical mechanism whereby EZH2 activates transcription.

    Evidence SANT2 domain-deletion mutants, ChIP for H3K27ac/me3, ATAC-seq, inflammasome activation assays, p53/SIRT1 competition assay

    PMID:35568718

    Open questions at the time
    • How EZH2 SANT2 domain promotes acetylation mechanistically (does it recruit an acetyltransferase?) not defined
    • Scope of SANT2-dependent activation genome-wide unknown
  21. 2022 High

    Identification of SMAD3 (K53, K333) and FOXA1 as direct EZH2 methylation substrates expanded the non-histone substrate repertoire and linked EZH2 catalytic activity to TGFβ-driven metastasis and DNA damage repair gene activation, respectively.

    Evidence In vitro methylation with MS site identification, mutagenesis, Co-IP with SARA, CRISPR screens, EZH2 inhibitor studies in CRPC

    PMID:35031563 PMID:35085106

    Open questions at the time
    • Complete non-histone substrate inventory unknown
    • Whether non-histone methylation requires PRC2 or is purely monomeric EZH2 not fully resolved
  22. 2023 High

    Identification of a non-canonical EZH2-cMyc complex at active gene promoters in multiple myeloma — distinct from PRC2 and degradable by an EZH2 PROTAC — demonstrated that PRC2-independent oncogenic functions are targetable.

    Evidence Co-IP, ChIP-seq distinguishing H3K27me3-negative EZH2 sites, PROTAC (MS177) treatment, in vivo MM models

    PMID:36747009

    Open questions at the time
    • Which EZH2 domain mediates cMyc interaction not mapped
    • Whether PROTAC degradation affects normal PRC2 function to cause toxicity not assessed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full scope of EZH2's non-histone substrate repertoire, the structural basis by which phosphorylation events coordinate the switch between repressor and activator conformations in different cancer contexts, and whether non-canonical EZH2 functions can be selectively targeted without disrupting canonical PRC2-mediated gene silencing.
  • Complete non-histone methylation substrate list undefined
  • No full-length structure of PRC2-independent EZH2 available
  • Selective pharmacological targeting of activator versus repressor EZH2 not achieved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 6 GO:0140110 transcription regulator activity 6 GO:0042393 histone binding 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0003723 RNA binding 2
Localization
GO:0005634 nucleus 4 GO:0005694 chromosome 3
Pathway
R-HSA-4839726 Chromatin organization 7 R-HSA-74160 Gene expression (Transcription) 6 R-HSA-1643685 Disease 4 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 2 R-HSA-168256 Immune System 2
Partners
DNMT1DNMT3AEEDOGTPRMT1SUZ12TP300USP7
Complex memberships
EZH2-cMyc non-canonical complexEZH2-p300 coactivator complexPRC2 (EZH2-EED-SUZ12-RbAp46/48)

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 EZH2 is the catalytic subunit of the EED-EZH2 (PRC2) complex and specifically methylates nucleosomal histone H3 at lysine 27 (H3K27); H3K27 methylation colocalizes with E(Z) at the Ultrabithorax Polycomb response element and correlates with Ubx repression; methylated H3K27 facilitates binding of Polycomb (PC/PRC1) to histone H3. Biochemical purification, in vitro histone methyltransferase assay on nucleosomes, chromatin immunoprecipitation (ChIP) Science High 12351676
2002 The human EZH2-containing PRC2 complex (also containing EED, SUZ12, and RbAp46/48) possesses histone methyltransferase activity targeting H3K9 and H3K27; enzymatic activity requires an intact SET domain in EZH2. Biochemical purification of multiprotein complex, in vitro histone methyltransferase assay, SET-domain mutagenesis Genes & development High 12435631
2002 EZH2 is overexpressed in hormone-refractory metastatic prostate cancer; siRNA knockdown of EZH2 inhibits prostate cell proliferation in vitro; ectopic EZH2 expression induces transcriptional repression of a cohort of genes requiring an intact SET domain and histone deacetylase activity. Gene expression profiling, siRNA knockdown, ectopic overexpression, SET-domain mutagenesis, HDAC inhibitor treatment Nature High 12374981
2003 EZH2 promotes neoplastic transformation of breast epithelial cells; EZH2-mediated cell invasion requires an intact SET domain and histone deacetylase activity; EZH2 overexpression confers anchorage-independent growth. Overexpression in immortalized mammary epithelial cells, SET-domain mutagenesis, HDAC inhibitor treatment, invasion assays, tissue microarray Proceedings of the National Academy of Sciences of the United States of America High 14500907
2003 EZH2 expression is regulated by the pRB-E2F pathway; EZH2 and EED are essential for proliferation of both transformed and non-transformed human cells; EZH2 ectopic expression provides a proliferative advantage to primary cells. RNA interference, ectopic overexpression in primary cells, pRB/E2F pathway perturbation, BrdU proliferation assay The EMBO journal High 14532106
2004 SUZ12 is essential for the enzymatic activity and stability of PRC2/3 complexes; Suz12-deficient embryos show a specific loss of di- and trimethylated H3K27, demonstrating that SUZ12 is required for EZH2 methyltransferase activity in vivo. Conditional mouse knockout, in vitro HMT assay, western blot for H3K27me2/3 in embryos and cells The EMBO journal High 15385962
2005 EZH2 interacts with DNA methyltransferases (DNMT1, DNMT3A, DNMT3B) within PRC2/3 complexes and associates with DNMT activity in vivo; binding of DNMTs to EZH2-repressed gene promoters depends on EZH2; EZH2 is required for DNA methylation at its target promoters, serving as a recruitment platform linking H3K27 methylation to DNA methylation. Co-immunoprecipitation, DNMT activity assay, ChIP, bisulfite genomic sequencing, siRNA knockdown Nature High 16357870
2007 EZH2-containing PRC2 binds throughout the INK4A-ARF locus and maintains H3K27me3 there; EZH2 downregulation during cellular senescence is accompanied by decreased H3K27me3, displacement of BMI1 (PRC1), and transcriptional activation of p16INK4A/p14ARF. ChIP, western blot for H3K27me3, siRNA knockdown, senescence model Genes & development High 17344414
2008 EZH1, a homolog of EZH2, is physically present in a noncanonical PRC2 complex and functions as an H3K27 methyltransferase in vitro and in vivo; EZH1 colocalizes with H3K27me3 on chromatin and preserves this mark on development-related genes in Ezh2-null ESCs; depletion of both EZH1 and EZH2 abolishes residual H3K27 methylation. Biochemical purification, in vitro HMT assay, ChIP, genetic knockout (Ezh2-/-ESCs), siRNA knockdown Molecular cell High 19026780
2008 PRC2-EZH2 catalyzes H3K27me2/3 and its knockdown reduces global H3K27me2/3 levels; PRC2-EZH1 performs H3K27 methylation weakly but instead directly compacts chromatin in the absence of the methyltransferase cofactor SAM, demonstrating mechanistically distinct repressive roles for EZH1 vs EZH2. In vitro HMT assay, siRNA knockdown, electron microscopy for chromatin compaction, quantitative western blot for H3K27me2/3 Molecular cell High 19026781
2008 microRNA-101 directly inhibits EZH2 expression and function; genomic loss of miR-101 loci occurs in a majority of metastatic prostate cancer cases, leading to EZH2 overexpression and epigenetic dysregulation. miRNA transfection/inhibition, luciferase reporter assay, genomic copy-number analysis (FISH), quantitative RT-PCR and western blot Science High 19008416
2010 Recurrent somatic gain-of-function mutations at EZH2 Y641 occur in follicular lymphoma and GCB-DLBCL; mutant Y641 EZH2 proteins show altered substrate specificity with reduced activity toward unmethylated H3K27 but enhanced trimethylation of already-mono/dimethylated H3K27, leading to global H3K27me3 hypermethylation. Targeted resequencing of lymphoma cohorts, in vitro histone methyltransferase assay with wild-type and mutant EZH2 Nature genetics High 20081860
2010 Inactivating (loss-of-function) EZH2 mutations occur in myeloid malignancies (MDS/MPN, myelofibrosis), demonstrating that EZH2 functions as a tumor suppressor in myeloid contexts; mutations cause premature chain termination or direct abrogation of histone methyltransferase activity. Sequencing of 614 myeloid malignancy patient samples, homozygosity mapping (uniparental disomy), in vitro HMT activity assays Nature genetics High 20601953
2010 TMPRSS2-ERG fusion directly activates EZH2 transcription in prostate cancer; EZH2 acts downstream of ERG to mediate epigenetic repression of AR-regulated differentiation genes, linking oncogenic ETS fusions to the PRC2 H3K27 methylation program. ChIP-seq, siRNA knockdown, gene expression profiling, ChIP-qPCR Cancer cell High 20478527
2010 HOTAIR lncRNA serves as a scaffold simultaneously binding PRC2 (via its 5' domain) and LSD1/CoREST (via its 3' domain), enabling RNA-mediated assembly of EZH2-containing PRC2 and LSD1 for coordinated H3K27 methylation and H3K4 demethylation at target genes. RNA pulldown, domain deletion mapping, RIP, ChIP, in vitro reconstitution of complex assembly Science High 20616235
2012 EZH2 functions as a transcriptional coactivator in castration-resistant prostate cancer (CRPC) cells independent of its role in PRC2-mediated gene repression; this non-canonical coactivation involves EZH2 acting as a cofactor for androgen receptor and other transcription factors, requires EZH2 phosphorylation, and depends on an intact methyltransferase domain. siRNA knockdown, ChIP-seq, transcriptome profiling, co-immunoprecipitation, phosphorylation-mimetic/dead mutants Science High 23239736
2014 O-GlcNAcylation of EZH2 at serine 75 by OGT stabilizes EZH2 protein and promotes PRC2 integrity; OGT depletion selectively reduces H3K27me3 by destabilizing EZH2; EZH2 S75A mutant shows reduced stability, confirming the site. Co-immunoprecipitation, cosedimentation, OGT knockdown, site-directed mutagenesis (S75A), western blot for H3K27me3, ChIP, microarray Proceedings of the National Academy of Sciences of the United States of America High 24474760
2016 EZH2 interacts with B2 SINE RNA and triggers its cleavage upon heat stress, releasing the B2 RNA 'speed bump' that normally suppresses RNA polymerase II elongation on stress-responsive genes; this function activates stress genes independently of EZH2 histone methyltransferase activity. RNA-protein interaction assays, EZH2 depletion/reconstitution, RNase cleavage assays, Pol II ChIP, nuclear run-on transcription Cell High 27984727
2017 EZH2 directly methylates the NKT lineage transcription factor PLZF (a non-histone substrate) in a chromatin-independent manner, promoting PLZF ubiquitination and degradation; T-cell-specific Ezh2 deletion causes NKT cell expansion with normal H3K27me3, while deletion of PRC2 components Suz12 or Eed ablates NKT development, confirming the non-canonical function is PRC2-independent. T-cell-specific conditional knockout (Ezh2, Suz12, Eed), in vitro methyltransferase assay on PLZF, Co-IP, ubiquitination assay, flow cytometry EMBO reports High 28223321
2018 Macrophage EZH2 mediates TLR-induced proinflammatory gene expression by repressing SOCS3 via H3K27me3; EZH2 deficiency upregulates SOCS3, enhancing K48-linked ubiquitination and degradation of TRAF6 and thereby impairing MyD88-dependent NF-κB activation; rescue by SOCS3 silencing restores macrophage activation. Myeloid-specific Ezh2 conditional knockout, ChIP for H3K27me3 at SOCS3 locus, ubiquitination assay, NF-κB reporter, SOCS3 silencing rescue experiments, colitis and EAE mouse models The Journal of experimental medicine High 29626115
2019 EZH2 loss combined with oncogenic NRASG12D induces myeloid leukemia by derepressing BCAT1, which catalyzes branched-chain amino acid (BCAA) transamination; reactivated BCAT1 sustains intracellular BCAA pools to enhance mTOR signaling in leukemia-initiating cells; genetic or pharmacologic BCAT1 inhibition selectively impairs EZH2-deficient leukemia cells. Conditional mouse knockout (EZH2 + NRASG12D), CRISPR, ChIP for H3K27me3 at BCAT1 locus, metabolomics, mTOR signaling assays, BCAT1 inhibitor treatment Cancer discovery High 31189531
2020 PRMT1 asymmetrically dimethylates EZH2 at R342; this meR342-EZH2 modification inhibits CDK1-mediated phosphorylation of EZH2 at T345 and T487, thereby attenuating TRAF6-mediated ubiquitylation and proteasomal degradation of EZH2, thus stabilizing EZH2. Co-immunoprecipitation, in vitro methylation assay, site-directed mutagenesis, ubiquitination assay, CDK1 kinase assay, mass spectrometry Cell death and differentiation High 32895488
2020 EZH2 harbors a partially disordered transactivation domain (TAD) comprising the SRM and SANT1 regions; the TAD can interact with the transcriptional coactivator p300/histone acetyltransferase; cancer-specific EZH2 phosphorylation events unlock the TAD to enable structural transitions and p300 binding, switching EZH2 from a gene repressor to an activator. Crystal structure of EZH2-EED binary complex, NMR characterization of TAD disorder, co-immunoprecipitation, reporter gene activation assay, phosphomimetic mutants Proceedings of the National Academy of Sciences of the United States of America High 32631994
2020 EZH2 phosphorylation at tyrosine 696 by nuclear Src kinase (pY696-EZH2) switches its binding preference from histone H3 to RNA polymerase II, converting EZH2 from a methyltransferase to a transcription factor that drives c-JUN expression and downstream G-CSF secretion to recruit immunosuppressive neutrophils. Phospho-specific antibody, Co-IP with RNA Pol II vs H3, ChIP, knockdown/reconstitution with phospho-mutants, cytokine measurement, brain metastasis mouse models Science translational medicine High 32461334
2020 USP7 deubiquitinates EZH2 and stabilizes it; USP7 knockdown reduces EZH2 protein levels and impairs EZH2-dependent transcriptional repression; restored EZH2 rescues cell migration, invasion, and sphere formation in USP7-depleted prostate cancer cells. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, ectopic EZH2 rescue experiment, cell functional assays Genetics and molecular biology Medium 32453339
2020 USP7 stabilizes EZH2 through deubiquitination; catalytically inactive USP7 mutant fails to alter EZH2 levels; USP7 overexpression promotes tumor growth and invasion in vivo via EZH2. Co-immunoprecipitation, ubiquitination assay, USP7 catalytic mutant, siRNA, xenograft mouse model American journal of cancer research Medium 32064169
2021 Cryo-EM structures of PRC2:EZH1 monomer and dimer bound to nucleosome reveal a dramatic conformational change upon nucleosome binding; a divergent EZH1/2 loop is essential for nucleosome binding, methyltransferase activity, and chromatin compaction; PRC2:EZH1 dimers are more effective than monomers at promoting chromatin compaction. Cryo-EM structure determination, mutagenesis of the divergent loop, in vitro HMT assay, nucleosome-binding assay, chromatin compaction assay Nature communications High 33514705
2021 PRMT5 physically interacts with EZH2 and cooperates to repress CDKN2B (p15INK4b) in colorectal cancer; PRMT5-mediated H4R3me2s and H3R8me2s marks at the CDKN2B promoter reduce CpG methylation when PRMT5 is lost; EZH2 binding and H3K27me3 at CDKN2B are enhanced by PRMT5 interaction. Co-immunoprecipitation, GST pulldown, ChIP-qPCR, bisulfite sequencing, siRNA knockdown, luciferase reporter Theranostics Medium 33664859
2022 EZH2 methylates SMAD3 at K53 and K333; this methylation facilitates SMAD3 membrane recruitment via interaction with SARA, sustaining TGFB1-receptor-mediated SMAD3 phosphorylation and activation; EZH2-mediated SMAD3 methylation promotes tumor metastasis. In vitro methyltransferase assay with recombinant EZH2 and SMAD3, mass spectrometry, site-directed mutagenesis (K53/K333), Co-IP with SARA, phosphorylation assay, cell invasion/metastasis assays, TAT peptide inhibition The Journal of clinical investigation High 35085106
2022 EZH2 inhibition blocks EZH2's transactivation (non-canonical coactivator) function in addition to its methyltransferase activity; EZH2 methylates the pioneer factor FOXA1 and interacts with p300 via its TAD to activate DNA damage repair (base excision repair) genes; EZH2 inhibitor treatment downregulates BER genes and sensitizes CRPC cells to genotoxic stress. EZH2 inhibitor treatment, CRISPR-Cas9 KO screens, gene expression and epigenomics profiling, Co-IP of EZH2-p300, FOXA1 methylation assay, clonogenic survival assays Proceedings of the National Academy of Sciences of the United States of America High 35031563
2022 EZH2 interacts with HP1BP3 in glioblastoma stem cells; the EZH2-HP1BP3 interaction impairs H3K9 methylation and co-activates WNT7B expression, promoting temozolomide resistance and stemness. Immunoprecipitation-mass spectrometry, Co-IP, ChIP, siRNA knockdown, TMZ resistance assays, sphere formation Oncogene Medium 36517590
2023 EZH2 interacts with cMyc in multiple myeloma cells, forming a non-canonical EZH2-cMyc complex that co-localizes with gene activation marks and promotes MM tumorigenesis independent of PRC2 and H3K27me3; both canonical EZH2-PRC2 and non-canonical EZH2-cMyc complexes can be degraded by the EZH2 PROTAC degrader MS177. Co-immunoprecipitation, ChIP-seq for EZH2 and H3K27me3, PROTAC degrader (MS177) treatment, gene expression profiling, in vitro and in vivo proliferation assays Oncogene High 36747009
2021 Ezh2 functions through its SANT2 domain to maintain H3K27 acetylation at the Neat1 lncRNA promoter—promoting chromatin accessibility and p65-mediated Neat1 transcription for inflammasome activation—independently of its canonical methyltransferase activity; p53 competes with Ezh2 for the same Neat1 promoter region and recruits SIRT1 for H3K27 deacetylation to suppress Neat1 transcription. Domain-deletion mutants of Ezh2, ChIP for H3K27ac/H3K27me3, ATAC-seq, Co-IP, luciferase reporter, macrophage inflammasome activation assays, p53/Sirt1 co-immunoprecipitation Cell death and differentiation High 35568718
2024 AKT inhibitors synergize with EZH2 inhibitors to drive basal-like TNBC cells into a more differentiated, luminal-like state and then kill them by activating mammary gland involution signals; neither agent alone achieves this differentiation, indicating cooperative epigenetic and signaling reprogramming. Combinatorial drug treatment in multiple TNBC in vivo models, single-cell RNA-seq, machine learning classifier, differentiation marker profiling Nature Medium 39385030

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science (New York, N.Y.) 3069 12351676
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2010 Long noncoding RNA as modular scaffold of histone modification complexes. Science (New York, N.Y.) 2707 20616235
2002 The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 2204 12374981
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2005 The Polycomb group protein EZH2 directly controls DNA methylation. Nature 1725 16357870
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2003 EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proceedings of the National Academy of Sciences of the United States of America 1365 14500907
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