enhancer of zeste homolog 2 protein


Summary: A histone-lysine N-methyltransferase and catalytic subunit of Polycomb Repressive Complex 2. It methylates LYSINE 9 (H3K9me) and LYSINE 27 (H3K27me) of HISTONE H3, leading to transcriptional repression of the affected target gene. EZH2 also methylates non-histone proteins such as GATA4 TRANSCRIPTION FACTOR and the nuclear receptor RORA. It regulates CIRCADIAN CLOCKS via histone methylation at the PROMOTER REGIONS of the circadian genes and its repressive activity is also important for the identity and differentiation of EMBRYONIC STEM CELLS.

Top Publications

  1. Vo B, Li C, Morgan M, Theurillat I, Finkelstein D, Wright S, et al. Inactivation of Ezh2 Upregulates Gfi1 and Drives Aggressive Myc-Driven Group 3 Medulloblastoma. Cell Rep. 2017;18:2907-2917 pubmed publisher
    ..Although negative regulation of Gfi1 by Ezh2 may restrain MB development, Gfi1 activation can bypass these effects. ..
  2. Fornaro L, Crea F, Masi G, Paolicchi E, Loupakis F, Graziano F, et al. EZH2 polymorphism and benefit from bevacizumab in colorectal cancer: another piece to the puzzle. Ann Oncol. 2012;23:1370-1 pubmed publisher
  3. Zhang Z, Lei A, Xu L, Chen L, Chen Y, Zhang X, et al. Similarity in gene-regulatory networks suggests that cancer cells share characteristics of embryonic neural cells. J Biol Chem. 2017;292:12842-12859 pubmed publisher
    ..This observed similarity in regulatory mechanisms suggests that cancer cells might share characteristics of embryonic neural cells. ..
  4. Xie L, Zhang Z, Tan Z, He R, Zeng X, Xie Y, et al. MicroRNA-124 inhibits proliferation and induces apoptosis by directly repressing EZH2 in gastric cancer. Mol Cell Biochem. 2014;392:153-9 pubmed
    ..Therefore, miR-124 shows tumor-suppressive activity and may be a new and useful approach of gastric cancer therapy. ..
  5. Chen J, Xu Y, Tao L, Pan Y, Zhang K, Wang R, et al. MiRNA-26a Contributes to the Acquisition of Malignant Behaviors of Doctaxel-Resistant Lung Adenocarcinoma Cells through Targeting EZH2. Cell Physiol Biochem. 2017;41:583-597 pubmed publisher
    ..MiR-26a/EZH2 signal pathway makes contribute to the malignant phenotype of docetaxel-resistant of LAD cells which indicated that miR-26a exerts pivotal functions in the molecular etiology of chemoresistant lung adenocarcinoma. ..
  6. Bodor C, O Riain C, Wrench D, Matthews J, Iyengar S, Tayyib H, et al. EZH2 Y641 mutations in follicular lymphoma. Leukemia. 2011;25:726-9 pubmed publisher
  7. Dupret B, Volkel P, Vennin C, Toillon R, Le Bourhis X, Angrand P. The histone lysine methyltransferase Ezh2 is required for maintenance of the intestine integrity and for caudal fin regeneration in zebrafish. Biochim Biophys Acta Gene Regul Mech. 2017;1860:1079-1093 pubmed publisher
    ..In addition, ezh2-deficient mutants fail to properly regenerate their spinal cord after caudal fin transection suggesting that Ezh2 and H3K27me3 methylation might also be involved in the process of regeneration in zebrafish. ..
  8. Stazi G, Zwergel C, Mai A, Valente S. EZH2 inhibitors: a patent review (2014-2016). Expert Opin Ther Pat. 2017;27:797-813 pubmed publisher
    ..Several issues are still to be settled, such as drug resistance and the importance of selectivity over EZH1 or somatic EZH2 mutants. ..
  9. Brown R, Konopka K, Weerasinghe P, Jaitly V, Dasgupta A, McGuire M, et al. Morphoproteomics Identifies SIRT1 and EZH2 Pathways as Commonalities in B-cell Acute Lymphoblastic Leukemia: Pathogenetic Implications and Opportunities for Therapeutic Intervention. Ann Clin Lab Sci. 2017;47:3-9 pubmed

More Information


  1. Kikuchi J, Koyama D, Wada T, Izumi T, Hofgaard P, Bogen B, et al. Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma. J Clin Invest. 2015;125:4375-90 pubmed publisher
  2. Zhongchao W, Liyuan F, Dan T, Cong Z, Shijun L. [Therapeutic effect of enhancer of Zeste homolog 2 inhibitor GSK343 on periodontitis by regulating macrophage differentiation]. Hua Xi Kou Qiang Yi Xue Za Zhi. 2017;35:264-268 pubmed publisher
    ..7??m1???????tnf-??inos?????????ezh2??gsk343??il-10?arg-1???????ezh2???gsk343????raw264.7???m1??m2????raw264.7????????????????lps????????????????ezh2???gsk343????raw264.7??????????????? ezh2???gsk343?????????????????????????????. ..
  3. Jacobsen J, Woodard J, Mandal M, Clark M, Bartom E, Sigvardsson M, et al. EZH2 Regulates the Developmental Timing of Effectors of the Pre-Antigen Receptor Checkpoints. J Immunol. 2017;198:4682-4691 pubmed publisher
    ..Our results uncover a crucial role for EZH2 in adaptive lymphocytes to control the developmental timing of effectors of the pre-Ag receptor checkpoints. ..
  4. Wang Y, Chen S, Karnezis A, Colborne S, Santos N, Lang J, et al. The histone methyltransferase EZH2 is a therapeutic target in small cell carcinoma of the ovary, hypercalcaemic type. J Pathol. 2017;242:371-383 pubmed publisher
    ..Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. ..
  5. Liu Y, Yu K, Li M, Zeng K, Wei J, Li X, et al. EZH2 overexpression in primary gastrointestinal diffuse large B-cell lymphoma and its association with the clinicopathological features. Hum Pathol. 2017;64:213-221 pubmed publisher
  6. Kwon H, Song K, Han C, Zhang J, Lu L, Chen W, et al. Epigenetic Silencing of miRNA-34a in Human Cholangiocarcinoma via EZH2 and DNA Methylation: Impact on Regulation of Notch Pathway. Am J Pathol. 2017;187:2288-2299 pubmed publisher
    ..Consequently, these signaling cascades may represent potential therapeutic targets for effective treatment of human CCA. ..
  7. Amirnasr A, Verdijk R, van Kuijk P, Taal W, Sleijfer S, Wiemer E. Expression and inhibition of BRD4, EZH2 and TOP2A in neurofibromas and malignant peripheral nerve sheath tumors. PLoS ONE. 2017;12:e0183155 pubmed publisher
    ..Clinical studies are necessary to ultimately prove the relevance of BRD4 and EZH2 inhibition as novel therapeutic strategies for MPNST. ..
  8. Huang S, Fantini D, Merrill B, Bagchi S, Guzman G, Raychaudhuri P. DDB2 Is a Novel Regulator of Wnt Signaling in Colon Cancer. Cancer Res. 2017;77:6562-6575 pubmed publisher
    ..Our results identify DDB2 as both a partner and regulator of Wnt signaling, with an important role in suppressing colon cancer development. Cancer Res; 77(23); 6562-75. ©2017 AACR. ..
  9. Shoucri B, Martinez E, Abreo T, Hung V, Moosova Z, Shioda T, et al. Retinoid X Receptor Activation Alters the Chromatin Landscape To Commit Mesenchymal Stem Cells to the Adipose Lineage. Endocrinology. 2017;158:3109-3125 pubmed publisher
    ..These data offer insights into the roles of RXR and EZH2 in MSC lineage specification and shed light on how endocrine-disrupting chemicals such as TBT can reprogram stem cell fate...
  10. Campbell R, Tummino P. Cancer epigenetics drug discovery and development: the challenge of hitting the mark. J Clin Invest. 2014;124:64-9 pubmed publisher
    ..We will also highlight recent successes in cancer epigenetics drug discovery and consider important factors for clinical success in this burgeoning area. ..
  11. Rinke J, Muller J, Blaess M, Chase A, Meggendorfer M, Schafer V, et al. Molecular characterization of EZH2 mutant patients with myelodysplastic/myeloproliferative neoplasms. Leukemia. 2017;31:1936-1943 pubmed publisher
    ..Some genes, such as CXXC5, ETS1 and VAV3 have previously been implied to have a role in leukemogenesis. Their precise role in MDS/MPN needs to be further investigated. ..
  12. Bratkowski M, Yang X, Liu X. Polycomb repressive complex 2 in an autoinhibited state. J Biol Chem. 2017;292:13323-13332 pubmed publisher
  13. Ciarapica R, Russo G, Verginelli F, Raimondi L, Donfrancesco A, Rota R, et al. Deregulated expression of miR-26a and Ezh2 in rhabdomyosarcoma. Cell Cycle. 2009;8:172-5 pubmed
  14. Mozhui K, Pandey A. Conserved effect of aging on DNA methylation and association with EZH2 polycomb protein in mice and humans. Mech Ageing Dev. 2017;162:27-37 pubmed publisher
    ..The conservation in both sequence and methylation patterns of the age-dependent CpGs indicate that the epigenetic clock is a fundamental feature of aging in mammals. ..
  15. Wagner T, Jung M. New lysine methyltransferase drug targets in cancer. Nat Biotechnol. 2012;30:622-3 pubmed publisher
  16. Yamagishi M, Uchimaru K. Targeting EZH2 in cancer therapy. Curr Opin Oncol. 2017;29:375-381 pubmed publisher
    ..The EZH2-mediated epigenome and subsequent transcriptome define cellular identity. Effective and specific strategies for the manipulation of EZH2/PRC2 may lead to the development of more precise cancer medicines. ..
  17. Veija T, Koljonen V, Bohling T, Kero M, Knuutila S, Sarhadi V. Aberrant expression of ALK and EZH2 in Merkel cell carcinoma. BMC Cancer. 2017;17:236 pubmed publisher
    ..High expression of ALK, CDKN2A and EZH2 was recorded in MCC tumors. No ALK fusion was seen by FISH analysis. Overexpression of EZH2 suggests its potential as a drug target in MCC. ..
  18. Guglielmelli P, Pacilli A, Rotunno G, Rumi E, Rosti V, Delaini F, et al. Presentation and outcome of patients with 2016 WHO diagnosis of prefibrotic and overt primary myelofibrosis. Blood. 2017;129:3227-3236 pubmed publisher
  19. Bernasconi E, Gaudio E, Lejeune P, Tarantelli C, Cascione L, Kwee I, et al. Preclinical evaluation of the BET bromodomain inhibitor BAY 1238097 for the treatment of lymphoma. Br J Haematol. 2017;178:936-948 pubmed publisher
    ..Our data also indicate the use of combination schemes targeting EZH2, mTOR and BTK alongside BET bromodomains. ..
  20. Kirby M, Ramaker R, Roberts B, Lasseigne B, Gunther D, Burwell T, et al. Genome-wide DNA methylation measurements in prostate tissues uncovers novel prostate cancer diagnostic biomarkers and transcription factor binding patterns. BMC Cancer. 2017;17:273 pubmed publisher
  21. Wang X, Goodrich K, Gooding A, Naeem H, Archer S, Paucek R, et al. Targeting of Polycomb Repressive Complex 2 to RNA by Short Repeats of Consecutive Guanines. Mol Cell. 2017;65:1056-1067.e5 pubmed publisher
    ..Collectively, the abundance of PRC2-binding RNA motifs rationalizes the promiscuous RNA binding of PRC2, and their enrichment at Polycomb target genes provides a means for RNA-mediated regulation. ..
  22. Ho T, Kapur P, Eckel Passow J, Christie A, Joseph R, Serie D, et al. Multicenter Validation of Enhancer of Zeste Homolog 2 Expression as an Independent Prognostic Marker in Localized Clear Cell Renal Cell Carcinoma. J Clin Oncol. 2017;35:3706-3713 pubmed publisher
    ..Further studies are required to incorporate molecular biomarkers into surveillance guidelines and adjuvant clinical trials...
  23. Tatton Brown K, Loveday C, Yost S, Clarke M, Ramsay E, Zachariou A, et al. Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability. Am J Hum Genet. 2017;100:725-736 pubmed publisher
    ..These data reveal insights into the genetic control of human growth and demonstrate that exome sequencing in OGID has a high diagnostic yield. ..
  24. Tao T, Chen M, Jiang R, Guan H, Huang Y, Su H, et al. Involvement of EZH2 in aerobic glycolysis of prostate cancer through miR-181b/HK2 axis. Oncol Rep. 2017;37:1430-1436 pubmed publisher
    ..Taken together, these findings provide the first evidence that EZH2/miR-181b/HK2 pathway plays a positive role in PCa development. Targeting this aberrantly activated pathway may provide a new therapeutic strategy against PCa. ..
  25. Barsotti A, Ryskin M, Rollins R. Epigenetic reprogramming in solid tumors: therapeutic implications of EZH2 gain-of-function mutations. Epigenomics. 2015;7:687-90 pubmed publisher
  26. Harms K, Chubb H, Zhao L, Fullen D, Bichakjian C, Johnson T, et al. Increased expression of EZH2 in Merkel cell carcinoma is associated with disease progression and poorer prognosis. Hum Pathol. 2017;67:78-84 pubmed publisher
    ..024). In addition, EZH2 was expressed at higher levels in nodal metastases compared to primary tumors (P=.005). Our data demonstrate that EZH2 has prognostic value and may play an oncogenic role in MCC. ..
  27. Tao J, Shi L, Huang L, Shi H, Chen H, Wang Y, et al. EZH2 is involved in silencing of WNT5A during epithelial-mesenchymal transition of colon cancer cell line. J Cancer Res Clin Oncol. 2017;143:2211-2219 pubmed publisher
    ..Our results indicate that EZH2 was essential for the silencing of WNT5A during TGF-?-induced epithelial-mesenchymal transition of colon cancer cells. ..
  28. Ma X, Hayes E, Biswas A, Seger C, Prizant H, Hammes S, et al. Androgens Regulate Ovarian Gene Expression Through Modulation of Ezh2 Expression and Activity. Endocrinology. 2017;158:2944-2954 pubmed publisher
  29. Su J, Zhang E, Han L, Yin D, Liu Z, He X, et al. Long noncoding RNA BLACAT1 indicates a poor prognosis of colorectal cancer and affects cell proliferation by epigenetically silencing of p15. Cell Death Dis. 2017;8:e2665 pubmed publisher
    ..Our results suggest that BLACAT1, as a cell cycle regulator, may serve as a potential target for colon cancer prevention and treatment in human CRC. ..
  30. Mohammad F, Weissmann S, Leblanc B, Pandey D, Højfeldt J, Comet I, et al. EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas. Nat Med. 2017;23:483-492 pubmed publisher
    ..Taken together, these results show that residual PRC2 activity is required for the proliferation of H3K27M-expressing DIPGs, and that inhibition of EZH2 is a potential therapeutic strategy for the treatment of these tumors. ..
  31. Prokopuk L, Stringer J, Hogg K, Elgass K, Western P. PRC2 is required for extensive reorganization of H3K27me3 during epigenetic reprogramming in mouse fetal germ cells. Epigenetics Chromatin. 2017;10:7 pubmed publisher
  32. Wang A, Juan A, Ko K, Tsai P, Zare H, Dell Orso S, et al. The Elongation Factor Spt6 Maintains ESC Pluripotency by Controlling Super-Enhancers and Counteracting Polycomb Proteins. Mol Cell. 2017;68:398-413.e6 pubmed publisher
    ..Thus, in addition to serving as a histone chaperone and transcription elongation factor, Spt6 counteracts repression by opposing H3K27me3 deposition at critical genomic regulatory regions. ..
  33. Gnad F, Doll S, Manning G, Arnott D, Zhang Z. Bioinformatics analysis of thousands of TCGA tumors to determine the involvement of epigenetic regulators in human cancer. BMC Genomics. 2015;16 Suppl 8:S5 pubmed publisher
    ..Our predictor uncovered one OG and several TSGs among ERGs. Expression analyses elucidated multiple dysregulated ERGs including EZH2 as member of a co-expressed cell cycle network. ..
  34. Arifuzzaman S, Das A, Kim S, Yoon T, Lee Y, Jung K, et al. Selective inhibition of EZH2 by a small molecule inhibitor regulates microglial gene expression essential for inflammation. Biochem Pharmacol. 2017;137:61-80 pubmed publisher
  35. Beca F, Kensler K, Glass B, Schnitt S, Tamimi R, Beck A. EZH2 protein expression in normal breast epithelium and risk of breast cancer: results from the Nurses' Health Studies. Breast Cancer Res. 2017;19:21 pubmed publisher
    ..These results provide further evidence that EZH2 expression in the normal breast epithelium is independently associated with breast cancer risk and might be used to assist in risk stratification for women with benign breast biopsies. ..
  36. Inari H, Suganuma N, Kawachi K, Yoshida T, Yamanaka T, Nakamura Y, et al. Expression of enhancer of zeste homolog 2 correlates with survival outcome in patients with metastatic breast cancer: exploratory study using primary and paired metastatic lesions. BMC Cancer. 2017;17:160 pubmed publisher
    ..EZH2 expression was significantly increased in metastatic lesions compared with primary lesions. High-level expression of EZH2 in metastatic lesions was associated with poorer OS outcomes after primary surgery and recurrence. ..
  37. Shortt J, Ott C, Johnstone R, Bradner J. A chemical probe toolbox for dissecting the cancer epigenome. Nat Rev Cancer. 2017;17:160-183 pubmed publisher
    ..By annotating these reagents, we aim to share our perspectives on an informative 'epigenomic toolbox' of broad utility to the research community. ..
  38. Gherardi S, Ripoche D, Mikaelian I, Chanal M, Teinturier R, Goehrig D, et al. Menin regulates Inhbb expression through an Akt/Ezh2-mediated H3K27 histone modification. Biochim Biophys Acta Gene Regul Mech. 2017;1860:427-437 pubmed publisher
    ..Our data suggests therefore that Menin could take an important part to the Ezh2-epigenetic repressive landscape in many cells and tissues through its capacity to modulate Akt phosphorylation. ..
  39. Grossmann V, Kohlmann A, Eder C, Haferlach C, Kern W, Cross N, et al. Molecular profiling of chronic myelomonocytic leukemia reveals diverse mutations in >80% of patients with TET2 and EZH2 being of high prognostic relevance. Leukemia. 2011;25:877-9 pubmed publisher
  40. Yoshida K, Toden S, Ravindranathan P, Han H, Goel A. Curcumin sensitizes pancreatic cancer cells to gemcitabine by attenuating PRC2 subunit EZH2, and the lncRNA PVT1 expression. Carcinogenesis. 2017;38:1036-1046 pubmed publisher
    ..Overall, this study indicates clinical relevance for combining curcumin with chemotherapy to overcome chemoresistance in PDAC...
  41. Chen X, Ma H, Wang Z, Zhang S, Yang H, Fang Z. EZH2 Palmitoylation Mediated by ZDHHC5 in p53-Mutant Glioma Drives Malignant Development and Progression. Cancer Res. 2017;77:4998-5010 pubmed publisher
    ..Taken together, our work highlighted ZDHHC5 as a candidate therapeutic target for management of p53-mutated gliomas. Cancer Res; 77(18); 4998-5010. ©2017 AACR. ..
  42. Schlacher K. PARPi focus the spotlight on replication fork protection in cancer. Nat Cell Biol. 2017;19:1309-1310 pubmed publisher
    ..This challenges the DNA repair dominance in synthetic lethality...
  43. Xia L, Huang W, Bellani M, Seidman M, Wu K, Fan D, et al. CHD4 Has Oncogenic Functions in Initiating and Maintaining Epigenetic Suppression of Multiple Tumor Suppressor Genes. Cancer Cell. 2017;31:653-668.e7 pubmed publisher
    ..High CHD4 and 8-OHdG levels plus low expression of TSGs strongly correlates with early disease recurrence and decreased overall survival. ..
  44. Lu Y, Liu W, Lu J, Liu Z, Li H, Liu G, et al. LncRNA UCA1 promotes renal cell carcinoma proliferation through epigenetically repressing p21 expression and negatively regulating miR-495. Tumour Biol. 2017;39:1010428317701632 pubmed publisher
    ..Overall, overexpression of urothelial carcinoma-associated 1 functions as an oncogene in renal cell carcinoma that may offer a novel therapeutic target for renal cell carcinoma patients. ..
  45. Ter Braak B, Siezen C, Lee J, Rao P, Voorhoeve C, Ruppin E, et al. Insulin-like growth factor 1 receptor activation promotes mammary gland tumor development by increasing glycolysis and promoting biomass production. Breast Cancer Res. 2017;19:14 pubmed publisher
    ..Overall, these data suggest that the decreased mammary gland tumor latency time caused by chronic IGF1R activation is related to modulation of tumor progression rather than increased tumor initiation. ..
  46. Bujisic B, de Gassart A, Tallant R, Demaria O, Zaffalon L, Chelbi S, et al. Impairment of both IRE1 expression and XBP1 activation is a hallmark of GCB DLBCL and contributes to tumor growth. Blood. 2017;129:2420-2428 pubmed publisher
    ..These findings indicate that IRE1-XBP1 downregulation distinguishes GCB DLBCL from other DLBCL subtypes and contributes to tumor growth. ..
  47. Liu S, Chen D, Shen W, Chen L, Yu A, Fu H, et al. EZH2 Mediates the Regulation of S100A4 on E-cadherin Expression and the Proliferation, Migration of Gastric Cancer Cells. Hepatogastroenterology. 2015;62:737-41 pubmed
    ..As a novel downstream target of S100A4, EZH2 mediates the inhibition of S100A4 on E-cadherin. The SET domain is important for EZH2 in mediating the cellular function of S100A4. ..
  48. Liu B, Pang B, Wang Q, Yang S, Gao T, Ding Q, et al. EZH2 upregulation correlates with tumor invasiveness, proliferation, and angiogenesis in human pituitary adenomas. Hum Pathol. 2017;66:101-107 pubmed publisher
    ..This is the first report to describe EZH2 overexpression in human PAs, especially invasive adenomas. Thus, EZH2 is a potentially useful diagnostic marker and pharmacotherapeutic target for invasive PAs. ..
  49. Vaz M, Hwang S, Kagiampakis I, Phallen J, Patil A, O Hagan H, et al. Chronic Cigarette Smoke-Induced Epigenomic Changes Precede Sensitization of Bronchial Epithelial Cells to Single-Step Transformation by KRAS Mutations. Cancer Cell. 2017;32:360-376.e6 pubmed publisher
    ..Thus, epigenetic abnormalities may prime for changing oncogene senescence to addiction for a single key oncogene involved in lung cancer initiation. ..
  50. Pawlyn C, Bright M, Buros A, Stein C, Walters Z, Aronson L, et al. Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control. Blood Cancer J. 2017;7:e549 pubmed publisher
    ..Our results suggest that EZH2 inhibition may be a potential therapeutic strategy for the treatment of myeloma and should be investigated in clinical studies. ..
  51. Blanco M, Guttman M. Re-evaluating the foundations of lncRNA-Polycomb function. EMBO J. 2017;36:964-966 pubmed publisher
  52. Huang M, Hou J, Wang Y, Xie M, Wei C, Nie F, et al. Long Noncoding RNA LINC00673 Is Activated by SP1 and Exerts Oncogenic Properties by Interacting with LSD1 and EZH2 in Gastric Cancer. Mol Ther. 2017;25:1014-1026 pubmed publisher
  53. Abdel Wahab O, Pardanani A, Patel J, Wadleigh M, Lasho T, Heguy A, et al. Concomitant analysis of EZH2 and ASXL1 mutations in myelofibrosis, chronic myelomonocytic leukemia and blast-phase myeloproliferative neoplasms. Leukemia. 2011;25:1200-2 pubmed publisher