Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

EZH2 (enhancer of zeste homolog 2 (Drosophila))

Written2014-03Amir Avan, Mina Maftouh, Hamid Fiuji, Elisa Giovannetti, Godefridus J Peters
Department of Medical Oncology, VU University Medical Center, Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands (AA, MM, EG, GJP); Department of New Sciences, Technology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran (AA); Department of Biochemistry, Faculty of Science, Payame Noor University, Mashhad, Iran (HF)

(Note : for Links provided by Atlas : click)


Other namesENX-1
HGNC (Hugo) EZH2
LocusID (NCBI) 2146
Atlas_Id 40517
Location 7q36.1
Location_base_pair Starts at 148504464 and ends at 148581441 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order Based on MapViewer, gene flanking EZH2 oriented on 7q35-q36 are:
- CUL1 (cullin 1); 7q36.1
- RNU7-20P (RNA, U7 small nuclear 20 pseudogene); 7q36.1
- EZH2; 7q35-q36.
  Figure 1. Location of EZH2 in chromosome 7, q35-36, which is located within 148504464 and 148581441 bp.
Fusion genes
(updated 2015)
EZH2 (7q36.1) / AUTS2 (7q11.22)GALNT11 (7q36.1) / EZH2 (7q36.1)


  Figure 2. The interaction and effect of EZH2 in regulation of transcriptional repression. Polycomb complex 2 (PRC2) exerts methyltransferase activity to H3K27 via the SET domain of the EZH2 subunit.
Description The EZH2 gene is located on chromosome 7, starting from 148504464 and ends at 148581441 bp. This gene encodes a member of the Polycomb-group (PcG) family. PcG family members form multimeric protein complexes, which are involved in maintaining the transcriptional repressive state of genes.
Transcription Multiple alternatively spliced transcript variants have been identified for this gene. These include 5 histone-lysine N-methyltransferase EZH2 isoforms (-a/-b/-c/-d/-e). The first variant (a) has the longest isoform of histone-lysine N-methyltransferase EZH2. The second variant (b) does not have an in-frame exon and an in-frame segment in the coding region, while (c) and (d) variants lack an in-frame segment in the coding region and two in-frame segments in the coding region, respectively, as compared to (a) variant. The last variant (e) has an alternate 5' UTR exon and lacks an in-frame exon and two in-frame segments in the coding region, as compared to (a) variant.


Description EZH2 protein is the catalytic subunit of Polycomb Repressive Complex 2, one of the two-multimeric repressive complexes in the organization of the PcG.
Function PcG proteins act as an important epigenetic mediator that can repress gene expression by forming multiple complexes leading to trimethylation at lysine 27 of histone H3 (H3K27me3; Cao et al., 2002; Viré et al., 2006). On the one hand, EZH2 is a histone methyltransferase, which plays an important role in tumor development (Santos-Rosa and Caldas, 2005). Moreover, this protein might also play essential roles in the control of central nervous systems by regulating the dopamine receptor D4 (Unland et al., 2014).
Homology The EZH2 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, fruit fly, and mosquito.


Note Several mutations have been reported in EZH2 gene, which has been shown to be associated with different human diseases (e.g., Weaver syndrome, lymphoma and myeloid neoplasms). In particular, Morin and collaborators, found that the mutation of EZH2 Y641, within the SET domain, is correlated with poor prognosis in myeloid neoplasms. They observed various heterozygous mutations at Y641 in 7% of follicular lymphomas and 22% of diffuse large cell B-cell lymphomas of germinal center origin (Morin et al., 2010), which increased the level of H3K27me3 (Chase and Cross, 2011). Furthermore EZH2 mutations have not yet been reported in several other human diseases such as pancreatic ductal adenocarcinoma, but we cannot exclude that such somatic alterations might occur.
Moreover, more than 4941 single nucleotide variations (SNPs) have been reported in the EZH2 gene (31th of January 2014, dbSNP), such as rs193921147, rs193921148, rs397515547, rs397515548, rs734004, rs12670401, rs6950683 etc.

Implicated in

Entity Human diseases
Note EZH2 is a histone methyltransferase, which is involved in the regulation of cell fate, and maintaining the balance between self-renewal and differentiation (Chang et al., 2011; Cao et al., 2002; Lund et al., 2014). This protein acts as an epigenetic mediator that can suppress gene expression by histones methylation at H3k27 (Cao et al., 2002; Viré et al., 2006). EZH2 is up-regulated in many tumors, such as breast and prostate cancer, which has been shown to be associated with tumor growth, invasion, and metastasis as well as poor prognosis (Santos-Rosa and Caldas, 2005; Chang and Hung, 2012).
Entity Pancreatic cancer
Note EZH2 is found to be overexpressed in a variety of carcinomas including pancreatic adenocarcinoma (PAC), and has been shown to be associated with decreased E-cadherin expression and poor prognosis in PAC patients (Toll et al., 2010). In particular, Toll and collaborators, evaluated the correlation of EZH2 with E-cadherin expression in 54 pancreatic adenocarcinomas, 13 intraductal papillary mucinous neoplasms (IPMN), and 6 chronic pancreatitis cases, and assessed response to gemcitabine in relation to EZH2 expression in tumor cells. This study showed that high EZH2 expression in pancreatic adenocarcinoma was significantly associated with decreased E-cadherin expression and more aggressive disease. Moreover, they also observed high EZH2 expression in IPMN tissue with moderate to severe dysplasia, but not in chronic pancreatitis.
In the study by Ougolkov and colleagues, EZH2 was identified as an important factor in pancreatic ductal adenocarcinoma (PDAC) cell chemoresistance. In particular, they showed that EZH2 depletion by RNA-interference sensitized PDAC cells to gemcitabine (Ougolkov et al., 2008). Furthermore, in our recent study, we showed that inhibition of EZH2 by EZH2 inhibitor DZNeP synergistically increased the antiproliferative activity of gemcitabine (first line agent in treatment of PDAC) through inhibition of cell proliferation and migration, and increasing apoptosis (Avan et al., 2012).
Entity Chronic pancreatitis
Note Mallen-St Clair and colleagues published an elegant study illustrating that the EZH2 connects pancreatitis to acinar cell regeneration, by providing a mechanism of protection against progression to cancerous lesions (Mallen-St Clair et al., 2012). In this study they showed that EZH2 is overexpressed in patients suffering from chronic pancreatitis. In particular, their findings revealed that EZH2 is constraining neoplastic progression through homeostatic mechanisms that control pancreatic regeneration (Mallen-St Clair et al., 2012).
Entity Prostate cancer
Note Varambally and collaborators, in 2002, demonstrated that EZH2 is up-regulated in hormone-refractory, metastatic prostate cancer. They found that small interfering RNA against EZH2 reduced the EZH2 protein expression in prostate cells and inhibited cell proliferation in vitro, while ectopic expression of EZH2 in prostate cells induces transcriptional repression of a specific cohort of genes. They also showed that EZH2 up-regulation was significantly associated with the progression of prostate cancer and poor clinical outcome (Varambally et al., 2002). Moreover, deletions of microRNA-101 in prostate cancer resulted as a negative regulator of EZH2 expression, providing a possible mechanism for EZH2 overexpression (Cao et al., 2010).
Entity Breast cancer
Note Kleer and collaborators explored the functional role of EZH2 in cancer cell invasion and breast cancer progression, and evaluated the expression of EZH2 in 280 patients. They showed that EZH2 transcript and protein were consistently elevated in invasive breast carcinoma compared to normal breast epithelia. Moreover, tissue microarray analysis illustrated that the levels of EZH2 expression were strongly associated with breast cancer aggressiveness. In particular, EZH2 overexpression in immortalized human mammary epithelial cell lines stimulated anchorage-independent growth and cell invasion in the cells. In this study they identified EZH2 as a marker of aggressive breast cancer, which promotes neoplastic transformation of breast epithelial cells (Kleer et al., 2003).
Entity Bladder carcinoma
Note Several studies have been shown the role of EZH2 in bladder carcinomas (Weikert et al., 2005; Raman et al., 2005; Arisan et al., 2005). In particular, Weikert and collaborators, evaluated the EZH2 expression in 37 bladder carcinomas using real-time reverse transcription-polymerase chain reaction (RT-PCR) and correlated the data with clinicopathological findings. They found that the mRNA levels of EZH2 were significantly higher in invasive bladder carcinomas (median value, 38.92) compared to non-invasive tumors (median value, 15.51). Moreover, the level of EZH2 expression was significantly higher in grade-3, with respect to grade-1/2 lesions, suggesting its role in the progression of bladder tumors. In addition, increased EZH2 expression correlated with oncogenesis of the bladder (Arisan et al., 2005; Weikert et al., 2005).
Entity Gastric cancer
Note Despite the complexity of stomach carcinogenesis, a number of markers identified as prognostic factors, including EZH2. Matsukawa and colleagues determined the expression of EZH2 in 83 surgically removed human gastric cancer tissues and analyzed its association with the clinicopathological features of human gastric cancers. Immunohistochemical analysis of the tissue samples and corresponding non-cancerous gastric mucosa demonstrated that EZH2 was more highly expressed in the cancerous than in the non-cancerous tissues, and the expression levels of EZH2 were markedly associated with tumor size, depth of invasion, vessel invasion, lymph node metastasis and clinical stages. Furthermore, gastric cancer patients with high-level EZH2 expression had poorer prognosis, compared to those expressing low levels of EZH2 (Matsukawa et al., 2006).
Entity Lung cancer
Note Several studies have investigated the biological role and prognostic value of EZH2 in lung cancer. Recently, Xia and colleagues demonstrated that inhibition of EZH2 by RNAi enhanced irradiation-induced inhibition of human lung cancer growth in vitro and in vivo. They showed that irradiation in combination with the inhibition of EZH2 arrested A549 cells in the G1-S boundary, inhibited cell proliferation, increased the percentage of apoptotic cells in vitro, and reduced tumor size and increased survival in tumor xenograft (Xia et al., 2012). Another study evaluated the EZH2 expression in 106 patients classified as stage I non-small cell lung cancer (NSCLC). They found that patients with positive EZH2 expression had a larger tumor size and survived significantly shorter, compared to the patients with low EZH2 expression. Moreover, in vitro studies showed that knockdown of EZH2 expression in the NSCLC cell lines reduced the tumor growth rate and invasive activity, indicating that EZH2 promotes progression and invasion of NSCLC, and its expression can be considered as a novel prognostic biomarker in NSCLC (Huqun et al., 2012).
Moreover, Lv and collaborators, in 2012 evaluated the expression of EZH2 in lung adenocarcinoma tissues and cell lines. They observed that EZH2 overexpression in tumor tissue significantly correlated with histological differentiation, pathological tumor-node-metastasis stage and smoking history. Moreover, overexpression of EZH2 was also detected in cisplatin-resistant cancer cells with respect to cisplatin-sensitive cells, while inhibition of EZH2 inhibited cell proliferation and migration, and induced apoptosis in both cisplatin-resistant and cisplatin-sensitive cell lines. These data suggested that EZH2 contributed to the progression of lung adenocarcinoma, and the suppression of EZH2 inhibited cell growth and sensitized cells to cisplatin in lung adenocarcinoma (Lv et al., 2012). Furthermore, Xu and collaborators, found a positive correlation between high EZH2 expression with pathologic stage, nodal involvement in lung cancer patients. In particular, they showed that overexpression of EZH2 was associated with reduced tissue inhibitor of metalloproteinase-3 expression, which was shown to be negatively associated with tumor metastasis in lung cancer (Xu et al., 2013).
Entity Hepatocellular carcinoma
Note Sudo and collaborators investigated the expression of EZH2 in 66 patients with hepatocellular carcinoma (HCC), using RT-PCR, and correlated its expression with clinicopathological parameters. They observed that the expression levels of EZH2 in tumor tissue specimens were significantly higher, compared to the non-tumor tissue specimens. Moreover, these analyses demonstrated that the incidence of cancer cell invasion into the portal vein was markedly increased in the group of patients with high EZH2 expression with respect to the patients with low EZH2 expression, while there was no difference in the disease-free survival rate between the two groups of patients (Sudo et al., 2005).
Entity Hematological malignancies
Note The role of EZH2 in hematological malignancies is still unclear. Several point mutations, resulting in gain-of-function, or inactivating mutations (loss-of-function), have been observed in lymphoma and leukemia, suggesting its role as an oncogene or tumor-suppressor gene. Visser and collaborators, evaluated the expression of both multimeric PcG protein complexes (EZH2-EED- and a BMI1-RING1- containing complex) in six cases of mantle cell lymphoma (MCL). They showed that MCL cells expressed BMI1-RING1, but not EZH2-EED, like normal mantle cells. Moreover, they showed that the up-regulation of EZH2 was associated with higher proliferation rate of haematopoietic cells (Visser et al., 2001).
A recent study performed a comparative microarray analysis of gene expression in primary adult T-cell leukemia/lymphoma samples. This study found the higher levels of EZH2, RING1 and YY1 binding protein transcripts with enhanced levels of H3K27m3 in adult T-cell leukemia/lymphoma cells, compared with those in normal CD4 (+) T cells. They also showed that patients with high EZH2 expression had a significantly poorer prognosis, indicating a possible role of this gene in the oncogenesis and progression of this disease (Sasaki et al., 2011). Another gene expression profiling of Polycomb, Hox and Meis genes in 126 patients with acute myeloid leukemia showed that the expression levels of EZH2 and MEL18 were significantly higher in patients with complex karyotype and lower in CBF-mutated patients. Moreover, comparisons between the PcG and PcG-regulated genes and clinical data demonstrated the correlations of genes involved in DNA methylation with apoptosis (BAX, Caspase 3) and multidrug-resistance (MDR1, MRP), suggesting the role of PcG and PcG-regulated genes in leukaemogenesis (Grubach et al., 2008). Moreover, Xu and collaborators examined a heterogeneous myelodysplastic syndrome (MDS)/AML population known to harbor DNA methylation of tumor-suppressor genes, such as p15INK4B. They observed that patients with p15INK4B gene methylation had a significantly higher expression of EZH2 with respect to the non-methylated counterparts, and the level of EZH2 expression correlated with poor clinical outcome (Xu et al., 2011).
Conversely, Nikoloski and collaborators demonstrated the role of EZH2 as tumor suppressor gene in myelodysplastic syndromes (MDS). In this study, they sequenced the EZH2 gene in 126 patients with MDS. These analyses revealed that EZH2 gene was frequently mutated in MDS patients. Similarly, another recent study demonstrated that inhibition of EZH2 increased the tumorigenic potential and mortality of T cell acute lymphoblastic leukemia cells transplanted into NOD-SCID mice, suggesting the tumor suppressor role of PRC2 in human leukemia (Ntziachristos et al., 2012).
Qi and collaborators recently developed an EZH2-selective small-molecule inhibitor EI1 that binds to the S-adenosylmethionine of EZH2. They observed that inhibition of EZH2 by EI1 in diffused large B-cell lymphomas cells carrying the Y641 mutations decreased the cell proliferation, cell cycle arrest, and enhanced apoptosis (Qi et al., 2012). Two other recent studies have demonstrated further advances in the therapeutic potential of EZH2 inhibition to treat lymphoma. Among the compounds, which have been developed so far, EPZ005687 and GSK126 have been found to induce apoptosis in lymphoma cell lines harboring Tyr641 mutations with minimal effect on WT cells, in vitro (Knutson et al., 2012) and in vivo (McCabe et al., 2012). In particular, McCabe and collaborators, showed that GSK126 molecule inhibited tumor growth and significantly increased survival of the mice carrying lymphoma cells (McCabe et al., 2012; Lund et al., 2014).
In aggregate, considering the dual function of EZH2, which has been shown to act as oncogene or tumor-suppressor gene in hematological malignancies, the therapeutic potential of EZH2 inhibitors should be evaluated carefully, to ensure achievement of beneficial effect, rather than tumorigenic effect (Lund et al., 2014).
Entity Pediatric tumors of the central nervous system
Note The dopamine receptor D4 (DRD4) is a G-protein-coupled receptor widely expressed throughout the central nervous system (CNS). Disruption of dopamine signaling is implied in diseases including schizophrenia, Parkinson's and Huntington's disease (Oak et al., 2000). Recently Unland and colleagues identified DRD4 as a methylated candidate in pediatric CNS tumors, using a genome-wide methylation approach. Their analyses suggested DRD4 as a direct target of EZH2. In particular, they showed that depletion of EZH2 is sufficient to induce re-expression of DRD4, suggesting the role of EZH2 for DNA hypermethylation in the epigenetic inhibition of DRD4 (Unland et al., 2014).
Entity Glioblastoma multiforme
Note Overexpression of the EZH2 has been observed in different malignancies, including glioblastoma multiforme (GBM) (Venneti et al., 2013). Suvà and collaborators demonstrated that disruption of EZH2 by DZNep, or its specific down-regulation by short hairpin RNA, strongly impairs GBM cancer stem cell self-renewal in vitro and tumor-initiating capacity in vivo. They also showed the direct transcriptional regulation of c-myc by EZH2, using genome-wide expression analysis of DZNep-treated GBM, suggesting its role as a valuable new therapeutic target for management of patients with GBM (Suvà et al., 2009).

To be noted

This study was partially supported by grants from Netherlands Organization for Scientific Research, VENI grant (Elisa Giovannetti), CCA Foundation 2012 (Amir Avan, Godefridus J Peters, Elisa Giovannetti), Iranian grant from Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran (Amir Avan), AIRC/Marie Curie International Fellowship (Elisa Giovannetti), and Istituto Toscano Tumori (Elisa Giovannetti).


The dopamine D(4) receptor: one decade of research.
Oak JN, Oldenhof J, Van Tol HH.
Eur J Pharmacol. 2000 Sep 29;405(1-3):303-27. (REVIEW)
PMID 11033337
The Polycomb group protein EZH2 is upregulated in proliferating, cultured human mantle cell lymphoma.
Visser HP, Gunster MJ, Kluin-Nelemans HC, Manders EM, Raaphorst FM, Meijer CJ, Willemze R, Otte AP.
Br J Haematol. 2001 Mar;112(4):950-8.
PMID 11298590
Role of histone H3 lysine 27 methylation in Polycomb-group silencing.
Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones RS, Zhang Y.
Science. 2002 Nov 1;298(5595):1039-43. Epub 2002 Sep 26.
PMID 12351676
The polycomb group protein EZH2 is involved in progression of prostate cancer.
Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, Ghosh D, Pienta KJ, Sewalt RG, Otte AP, Rubin MA, Chinnaiyan AM.
Nature. 2002 Oct 10;419(6907):624-9.
PMID 12374981
EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells.
Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, Ghosh D, Sewalt RG, Otte AP, Hayes DF, Sabel MS, Livant D, Weiss SJ, Rubin MA, Chinnaiyan AM.
Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11606-11. Epub 2003 Sep 19.
PMID 14500907
Increased expression of EZH2, a polycomb group protein, in bladder carcinoma.
Arisan S, Buyuktuncer ED, Palavan-Unsal N, Cas,kurlu T, Cakir OO, Ergenekon E.
Urol Int. 2005;75(3):252-7.
PMID 16215315
Increased expression of the polycomb group gene, EZH2, in transitional cell carcinoma of the bladder.
Raman JD, Mongan NP, Tickoo SK, Boorjian SA, Scherr DS, Gudas LJ.
Clin Cancer Res. 2005 Dec 15;11(24 Pt 1):8570-6.
PMID 16361539
Chromatin modifier enzymes, the histone code and cancer.
Santos-Rosa H, Caldas C.
Eur J Cancer. 2005 Nov;41(16):2381-402. Epub 2005 Oct 13. (REVIEW)
PMID 16226460
Clinicopathological significance of EZH2 mRNA expression in patients with hepatocellular carcinoma.
Sudo T, Utsunomiya T, Mimori K, Nagahara H, Ogawa K, Inoue H, Wakiyama S, Fujita H, Shirouzu K, Mori M.
Br J Cancer. 2005 May 9;92(9):1754-8.
PMID 15856046
Expression levels of the EZH2 polycomb transcriptional repressor correlate with aggressiveness and invasive potential of bladder carcinomas.
Weikert S, Christoph F, Kollermann J, Muller M, Schrader M, Miller K, Krause H.
Int J Mol Med. 2005 Aug;16(2):349-53.
PMID 16012774
Expression of the enhancer of zeste homolog 2 is correlated with poor prognosis in human gastric cancer.
Matsukawa Y, Semba S, Kato H, Ito A, Yanagihara K, Yokozaki H.
Cancer Sci. 2006 Jun;97(6):484-91.
PMID 16734726
The Polycomb group protein EZH2 directly controls DNA methylation.
Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden JM, Bollen M, Esteller M, Di Croce L, de Launoit Y, Fuks F.
Nature. 2006 Feb 16;439(7078):871-4. Epub 2005 Dec 14.
PMID 16357870
Gene expression profiling of Polycomb, Hox and Meis genes in patients with acute myeloid leukaemia.
Grubach L, Juhl-Christensen C, Rethmeier A, Olesen LH, Aggerholm A, Hokland P, Ostergaard M.
Eur J Haematol. 2008 Aug;81(2):112-22. doi: 10.1111/j.1600-0609.2008.01083.x. Epub 2008 Jun 28.
PMID 18410541
Regulation of pancreatic tumor cell proliferation and chemoresistance by the histone methyltransferase enhancer of zeste homologue 2.
Ougolkov AV, Bilim VN, Billadeau DD.
Clin Cancer Res. 2008 Nov 1;14(21):6790-6. doi: 10.1158/1078-0432.CCR-08-1013.
PMID 18980972
EZH2 is essential for glioblastoma cancer stem cell maintenance.
Suva ML, Riggi N, Janiszewska M, Radovanovic I, Provero P, Stehle JC, Baumer K, Le Bitoux MA, Marino D, Cironi L, Marquez VE, Clement V, Stamenkovic I.
Cancer Res. 2009 Dec 15;69(24):9211-8. doi: 10.1158/0008-5472.CAN-09-1622.
PMID 19934320
MicroRNA-101 negatively regulates Ezh2 and its expression is modulated by androgen receptor and HIF-1alpha/HIF-1beta.
Cao P, Deng Z, Wan M, Huang W, Cramer SD, Xu J, Lei M, Sui G.
Mol Cancer. 2010 May 17;9:108. doi: 10.1186/1476-4598-9-108.
PMID 20478051
Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin.
Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R, Paul JE, Boyle M, Woolcock BW, Kuchenbauer F, Yap D, Humphries RK, Griffith OL, Shah S, Zhu H, Kimbara M, Shashkin P, Charlot JF, Tcherpakov M, Corbett R, Tam A, Varhol R, Smailus D, Moksa M, Zhao Y, Delaney A, Qian H, Birol I, Schein J, Moore R, Holt R, Horsman DE, Connors JM, Jones S, Aparicio S, Hirst M, Gascoyne RD, Marra MA.
Nat Genet. 2010 Feb;42(2):181-5. doi: 10.1038/ng.518. Epub 2010 Jan 17.
PMID 20081860
Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes.
Nikoloski G, Langemeijer SM, Kuiper RP, Knops R, Massop M, Tonnissen ER, van der Heijden A, Scheele TN, Vandenberghe P, de Witte T, van der Reijden BA, Jansen JH.
Nat Genet. 2010 Aug;42(8):665-7. doi: 10.1038/ng.620. Epub 2010 Jul 4.
PMID 20601954
Implications of enhancer of zeste homologue 2 expression in pancreatic ductal adenocarcinoma.
Toll AD, Dasgupta A, Potoczek M, Yeo CJ, Kleer CG, Brody JR, Witkiewicz AK.
Hum Pathol. 2010 Sep;41(9):1205-9. doi: 10.1016/j.humpath.2010.03.004. Epub 2010 Jun 22.
PMID 20573371
EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-beta-catenin signaling.
Chang CJ, Yang JY, Xia W, Chen CT, Xie X, Chao CH, Woodward WA, Hsu JM, Hortobagyi GN, Hung MC.
Cancer Cell. 2011 Jan 18;19(1):86-100. doi: 10.1016/j.ccr.2010.10.035. Epub 2011 Jan 6.
PMID 21215703
Aberrations of EZH2 in cancer.
Chase A, Cross NC.
Clin Cancer Res. 2011 May 1;17(9):2613-8. doi: 10.1158/1078-0432.CCR-10-2156. Epub 2011 Mar 2. (REVIEW)
PMID 21367748
Overexpression of Enhancer of zeste homolog 2 with trimethylation of lysine 27 on histone H3 in adult T-cell leukemia/lymphoma as a target for epigenetic therapy.
Sasaki D, Imaizumi Y, Hasegawa H, Osaka A, Tsukasaki K, Choi YL, Mano H, Marquez VE, Hayashi T, Yanagihara K, Moriwaki Y, Miyazaki Y, Kamihira S, Yamada Y.
Haematologica. 2011 May;96(5):712-9. doi: 10.3324/haematol.2010.028605. Epub 2011 Jan 12.
PMID 21228036
Overexpression of the EZH2, RING1 and BMI1 genes is common in myelodysplastic syndromes: relation to adverse epigenetic alteration and poor prognostic scoring.
Xu F, Li X, Wu L, Zhang Q, Yang R, Yang Y, Zhang Z, He Q, Chang C.
Ann Hematol. 2011 Jun;90(6):643-53. doi: 10.1007/s00277-010-1128-5. Epub 2010 Dec 2.
PMID 21125401
Molecular mechanisms involved in the synergistic interaction of the EZH2 inhibitor 3-deazaneplanocin A with gemcitabine in pancreatic cancer cells.
Avan A, Crea F, Paolicchi E, Funel N, Galvani E, Marquez VE, Honeywell RJ, Danesi R, Peters GJ, Giovannetti E.
Mol Cancer Ther. 2012 Aug;11(8):1735-46. doi: 10.1158/1535-7163.MCT-12-0037. Epub 2012 May 23.
PMID 22622284
The role of EZH2 in tumour progression.
Chang CJ, Hung MC.
Br J Cancer. 2012 Jan 17;106(2):243-7. doi: 10.1038/bjc.2011.551. Epub 2011 Dec 20. (REVIEW)
PMID 22187039
Enhancer of zeste homolog 2 is a novel prognostic biomarker in nonsmall cell lung cancer.
Huqun, Ishikawa R, Zhang J, Miyazawa H, Goto Y, Shimizu Y, Hagiwara K, Koyama N.
Cancer. 2012 Mar 15;118(6):1599-606. doi: 10.1002/cncr.26441. Epub 2011 Aug 11.
PMID 21837672
A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells.
Knutson SK, Wigle TJ, Warholic NM, Sneeringer CJ, Allain CJ, Klaus CR, Sacks JD, Raimondi A, Majer CR, Song J, Scott MP, Jin L, Smith JJ, Olhava EJ, Chesworth R, Moyer MP, Richon VM, Copeland RA, Keilhack H, Pollock RM, Kuntz KW.
Nat Chem Biol. 2012 Nov;8(11):890-6. doi: 10.1038/nchembio.1084. Epub 2012 Sep 30.
PMID 23023262
The expression and significance of the enhancer of zeste homolog 2 in lung adenocarcinoma.
Lv Y, Yuan C, Xiao X, Wang X, Ji X, Yu H, Wu Z, Zhang J.
Oncol Rep. 2012 Jul;28(1):147-54. doi: 10.3892/or.2012.1787. Epub 2012 Apr 26.
PMID 22552406
EZH2 couples pancreatic regeneration to neoplastic progression.
Mallen-St Clair J, Soydaner-Azeloglu R, Lee KE, Taylor L, Livanos A, Pylayeva-Gupta Y, Miller G, Margueron R, Reinberg D, Bar-Sagi D.
Genes Dev. 2012 Mar 1;26(5):439-44. doi: 10.1101/gad.181800.111.
PMID 22391448
EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations.
McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS, Liu Y, Graves AP, Della Pietra A 3rd, Diaz E, LaFrance LV, Mellinger M, Duquenne C, Tian X, Kruger RG, McHugh CF, Brandt M, Miller WH, Dhanak D, Verma SK, Tummino PJ, Creasy CL.
Nature. 2012 Dec 6;492(7427):108-12. doi: 10.1038/nature11606. Epub 2012 Oct 10.
PMID 23051747
Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia.
Ntziachristos P, Tsirigos A, Van Vlierberghe P, Nedjic J, Trimarchi T, Flaherty MS, Ferres-Marco D, da Ros V, Tang Z, Siegle J, Asp P, Hadler M, Rigo I, De Keersmaecker K, Patel J, Huynh T, Utro F, Poglio S, Samon JB, Paietta E, Racevskis J, Rowe JM, Rabadan R, Levine RL, Brown S, Pflumio F, Dominguez M, Ferrando A, Aifantis I.
Nat Med. 2012 Feb 6;18(2):298-301. doi: 10.1038/nm.2651.
PMID 22237151
Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation.
Qi W, Chan H, Teng L, Li L, Chuai S, Zhang R, Zeng J, Li M, Fan H, Lin Y, Gu J, Ardayfio O, Zhang JH, Yan X, Fang J, Mi Y, Zhang M, Zhou T, Feng G, Chen Z, Li G, Yang T, Zhao K, Liu X, Yu Z, Lu CX, Atadja P, Li E.
Proc Natl Acad Sci U S A. 2012 Dec 26;109(52):21360-5. doi: 10.1073/pnas.1210371110. Epub 2012 Dec 10.
PMID 23236167
EZH2 silencing with RNAi enhances irradiation-induced inhibition of human lung cancer growth in vitro and in vivo.
Xia H, Yu CH, Zhang Y, Yu J, Li J, Zhang W, Zhang B, Li Y, Guo N.
Oncol Lett. 2012 Jul;4(1):135-140. Epub 2012 Apr 26.
PMID 22807976
Evaluation of histone 3 lysine 27 trimethylation (H3K27me3) and enhancer of Zest 2 (EZH2) in pediatric glial and glioneuronal tumors shows decreased H3K27me3 in H3F3A K27M mutant glioblastomas.
Venneti S, Garimella MT, Sullivan LM, Martinez D, Huse JT, Heguy A, Santi M, Thompson CB, Judkins AR.
Brain Pathol. 2013 Sep;23(5):558-64. doi: 10.1111/bpa.12042. Epub 2013 Mar 6.
PMID 23414300
EZH2 regulates cancer cell migration through repressing TIMP-3 in non-small cell lung cancer.
Xu C, Hou Z, Zhan P, Zhao W, Chang C, Zou J, Hu H, Zhang Y, Yao X, Yu L, Yan J.
Med Oncol. 2013 Dec;30(4):713. doi: 10.1007/s12032-013-0713-6. Epub 2013 Oct 17.
PMID 24132606
EZH2 in normal and malignant hematopoiesis.
Lund K, Adams PD, Copland M.
Leukemia. 2014 Jan;28(1):44-9. doi: 10.1038/leu.2013.288. Epub 2013 Oct 7. (REVIEW)
PMID 24097338
Epigenetic repression of the dopamine receptor D4 in pediatric tumors of the central nervous system.
Unland R, Kerl K, Schlosser S, Farwick N, Plagemann T, Lechtape B, Clifford SC, Kreth JH, Gerss J, Muhlisch J, Richter GH, Hasselblatt M, Fruhwald MC.
J Neurooncol. 2014 Jan;116(2):237-49. doi: 10.1007/s11060-013-1313-1. Epub 2013 Nov 22.
PMID 24264533


This paper should be referenced as such :
A Avan, M Maftouh, H Fiuji, E Giovannetti, GJ Peters
EZH2 (enhancer of zeste homolog 2 (Drosophila))
Atlas Genet Cytogenet Oncol Haematol. 2014;18(12):900-906.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other Leukemias implicated (Data extracted from papers in the Atlas) [36219+1]
  Classification of myelodysplastic syndromes 2015
Chronic Myelomonocytic Leukemia (CMML)
t(2;8)(p23;p11) KAT6A/ASXL2

Other Solid tumors implicated (Data extracted from papers in the Atlas)
  Prostate tumors: an overview

Other Cancer prone implicated (Data extracted from papers in the Atlas)
  Weaver syndrome

External links

HGNC (Hugo)EZH2   3527
Entrez_Gene (NCBI)EZH2  2146  enhancer of zeste 2 polycomb repressive complex 2 subunit
GeneCards (Weizmann)EZH2
Ensembl hg19 (Hinxton)ENSG00000106462 [Gene_View]  chr7:148504464-148581441 [Contig_View]  EZH2 [Vega]
Ensembl hg38 (Hinxton)ENSG00000106462 [Gene_View]  chr7:148504464-148581441 [Contig_View]  EZH2 [Vega]
ICGC DataPortalENSG00000106462
TCGA cBioPortalEZH2
AceView (NCBI)EZH2
Genatlas (Paris)EZH2
SOURCE (Princeton)EZH2
Genomic and cartography
GoldenPath hg19 (UCSC)EZH2  -     chr7:148504464-148581441 -  7q35-q36   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)EZH2  -     7q35-q36   [Description]    (hg38-Dec_2013)
EnsemblEZH2 - 7q35-q36 [CytoView hg19]  EZH2 - 7q35-q36 [CytoView hg38]
Mapping of homologs : NCBIEZH2 [Mapview hg19]  EZH2 [Mapview hg38]
OMIM277590   601573   
Gene and transcription
Genbank (Entrez)AB208895 AK092676 AK293239 AK302216 AK303585
RefSeq transcript (Entrez)NM_001203247 NM_001203248 NM_001203249 NM_004456 NM_152998
RefSeq genomic (Entrez)NC_000007 NC_018918 NG_032043 NT_007933 NW_004929333
Consensus coding sequences : CCDS (NCBI)EZH2
Cluster EST : UnigeneHs.732308 [ NCBI ]
CGAP (NCI)Hs.732308
Alternative Splicing : Fast-db (Paris)GSHG0028690
Alternative Splicing GalleryENSG00000106462
Gene ExpressionEZH2 [ NCBI-GEO ]     EZH2 [ SEEK ]   EZH2 [ MEM ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)2146
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ15910 (Uniprot)
NextProtQ15910  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ15910
Splice isoforms : SwissVarQ15910 (Swissvar)
Catalytic activity : Enzyme2.1.1.43 [ Enzyme-Expasy ] [ IntEnz-EBI ] [ BRENDA ] [ KEGG ]   
Domaine pattern : Prosite (Expaxy)CXC (PS51633)    SET (PS50280)   
Domains : Interpro (EBI)CXC_dom    EZH2_WD-Binding    SANT/Myb    SET_dom   
Domain families : Pfam (Sanger)EZH2_WD-Binding (PF11616)    SET (PF00856)   
Domain families : Pfam (NCBI)pfam11616    pfam00856   
Domain families : Smart (EMBL)SANT (SM00717)  SET (SM00317)  
DMDM Disease mutations2146
Blocks (Seattle)EZH2
PDB (SRS)2C6V    4MI0    4MI5   
PDB (PDBSum)2C6V    4MI0    4MI5   
PDB (IMB)2C6V    4MI0    4MI5   
PDB (RSDB)2C6V    4MI0    4MI5   
Structural Biology KnowledgeBase2C6V    4MI0    4MI5   
SCOP (Structural Classification of Proteins)2C6V    4MI0    4MI5   
CATH (Classification of proteins structures)2C6V    4MI0    4MI5   
Human Protein AtlasENSG00000106462
Peptide AtlasQ15910
IPIIPI00947357   IPI00376787   IPI00171252   IPI00947348   IPI00945286   IPI00941520   IPI00935586   IPI00946998   
Protein Interaction databases
IntAct (EBI)Q15910
Ontologies - Pathways
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  nuclear chromatin  core promoter binding  DNA binding  chromatin binding  protein binding  nucleus  nucleoplasm  nucleoplasm  cytoplasm  chromatin organization  transcription, DNA-templated  regulation of transcription, DNA-templated  gene expression  positive regulation of epithelial to mesenchymal transition  protein-lysine N-methyltransferase activity  histone-lysine N-methyltransferase activity  histone-lysine N-methyltransferase activity  chromatin DNA binding  ESC/E(Z) complex  regulation of gene expression, epigenetic  histone methyltransferase activity  regulation of circadian rhythm  positive regulation of MAP kinase activity  positive regulation of GTPase activity  negative regulation of gene expression, epigenetic  negative regulation of gene expression, epigenetic  negative regulation of transcription, DNA-templated  histone methyltransferase activity (H3-K27 specific)  negative regulation of retinoic acid receptor signaling pathway  rhythmic process  histone H3-K27 methylation  positive regulation of protein serine/threonine kinase activity  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  nuclear chromatin  core promoter binding  DNA binding  chromatin binding  protein binding  nucleus  nucleoplasm  nucleoplasm  cytoplasm  chromatin organization  transcription, DNA-templated  regulation of transcription, DNA-templated  gene expression  positive regulation of epithelial to mesenchymal transition  protein-lysine N-methyltransferase activity  histone-lysine N-methyltransferase activity  histone-lysine N-methyltransferase activity  chromatin DNA binding  ESC/E(Z) complex  regulation of gene expression, epigenetic  histone methyltransferase activity  regulation of circadian rhythm  positive regulation of MAP kinase activity  positive regulation of GTPase activity  negative regulation of gene expression, epigenetic  negative regulation of gene expression, epigenetic  negative regulation of transcription, DNA-templated  histone methyltransferase activity (H3-K27 specific)  negative regulation of retinoic acid receptor signaling pathway  rhythmic process  histone H3-K27 methylation  positive regulation of protein serine/threonine kinase activity  
Pathways : BIOCARTAThe PRC2 Complex Sets Long-term Gene Silencing Through Modification of Histone Tails [Genes]   
Pathways : KEGGMicroRNAs in cancer   
REACTOMEQ15910 [protein]
REACTOME PathwaysR-HSA-2559580 Oxidative Stress Induced Senescence [pathway]
REACTOME PathwaysR-HSA-3214841 PKMTs methylate histone lysines [pathway]
REACTOME PathwaysR-HSA-212300 PRC2 methylates histones and DNA [pathway]
Protein Interaction DatabaseEZH2
Atlas of Cancer Signalling NetworkEZH2
Wikipedia pathwaysEZH2
Orthology - Evolution
GeneTree (enSembl)ENSG00000106462
Phylogenetic Trees/Animal Genes : TreeFamEZH2
Gene fusions - Rearrangements
Fusion : MitelmanEZH2/AUTS2 [7q36.1/7q11.22]  
Fusion : MitelmanGALNT11/EZH2 [7q36.1/7q36.1]  [t(7;7)(q36;q36)]  
Fusion: TCGAEZH2 7q36.1 AUTS2 7q11.22 LUSC
Fusion: TCGAGALNT11 7q36.1 EZH2 7q36.1 LUAD
Polymorphisms : SNP, variants
NCBI Variation ViewerEZH2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)EZH2
Exome Variant ServerEZH2
SNP (GeneSNP Utah)EZH2
Genetic variants : HAPMAPEZH2
Genomic Variants (DGV)EZH2 [DGVbeta]
ICGC Data PortalEZH2 
TCGA Data PortalEZH2 
Tumor PortalEZH2
TCGA Copy Number PortalEZH2
Cancer Gene: CensusEZH2 
Somatic Mutations in Cancer : COSMICEZH2 
intOGen PortalEZH2
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)Mendelian genes
BioMutasearch EZH2
DgiDB (Drug Gene Interaction Database)EZH2
DoCM (Curated mutations)EZH2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)EZH2 (select a term)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
DECIPHER (Syndromes)7:148504464-148581441
CONAN: Copy Number AnalysisEZH2 
Mutations and Diseases : HGMDEZH2
OMIM277590    601573   
NextProtQ15910 [Medical]
Huge Navigator EZH2 [HugePedia]  EZH2 [HugeCancerGEM]
snp3D : Map Gene to Disease2146
BioCentury BCIQEZH2
General knowledge
Homologs : HomoloGeneEZH2
Homology/Alignments : Family Browser (UCSC)EZH2
Chemical/Protein Interactions : CTD2146
Chemical/Pharm GKB GenePA27939
Drug Sensitivity EZH2
Clinical trialEZH2
Other databases
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Fri Jan 29 18:24:09 CET 2016

Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us