EZH2

From Compendium of Cancer Genome Aberrations
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Primary Author(s)*

Paul De Fazio, MSc, Monash Health

Synonyms

  • Enhancer Of Zeste Homolog 2
  • Enhancer Of Zeste 2 Polycomb Repressive Complex 2 Subunit
  • ENX1
  • EZH1
  • KMT6
  • KMT6A

Genomic Location

Cytoband: 7q36.1

Genomic Coordinates:

chr7:148,504,464-148,581,441 [hg19]

chr7:148,807,372-148,884,349 [hg38]

Cancer Category/Type

Diffuse large B-cell lymphoma

EZH2 gain-of-function mutations affecting residue Tyr646 (NM_004456.4) occur in up to 22% of diffuse large B-cell lymphoma (DLBCL) of the germinal center B-cell (GCB) subtype, but not the activated B-cell (ABC) subtype (Morin et al., 2010; Reddy et al., 2017). Less commonly, mutations in Ala677 (NM_004456.4) and Ala687 (NM_004456.4) among other residues have also been described (Majer et al., 2012; McCabe et al., 2012). EZH2 Tyr646 mutations are more common in BCL2-rearranged GCB DLBCL (Ryan et al., 2011). The EZH2 inhibitor tazemetostat is undergoing clinical trials for use in relapsed or refractory B-cell lymphoma (Italiano et al., 2018).

Follicular Lymphoma

EZH2 Tyr646 (NM_004456.4) gain-of-function mutations affect 7-27% of follicular lymphomas (FL) (Bödör et al., 2013; Morin et al., 2010). Other mutations observed include Lys634, Val637, Val679, Ala682, and Ala692 (all NM_004456.4) (Bödör et al., 2013). Mutational status does not appear to affect overall survival (Bödör et al., 2013). Most mutations are monoallelic, predominantly clonal rather than subclonal events, and persist during transformation of FL and so are likely early events in this malignancy (Bödör et al., 2013).

Natural Killer/T-cell Lymphoma

EZH2 is highly expressed in many natural killer/T-cell lymphomas (Abdalkader et al., 2016; Kim et al., 2016), but gain-of-function mutations are not observed. EZH2 overexpression confers growth advantage in nasal-type natural killer/T-cell lymphomas independently of its histone methyltransferase activity, partly due to MYC-mediated inhibition of microRNAs that target EZH2 (Yan et al., 2013).

T-cell Acute Lymphoblastic Leukemia

Loss of function mutations and deletions affecting EZH2 occur in 25% of T-cell acute lymphoblastic leukemia (Ntziachristos et al., 2012).

Acute Myeloid Leukemia (AML) and Related Precursor Neoplasms

EZH2 is highly expressed in AML, particularly in patients with complex karyotypes (Grubach et al., 2008), and is associated with extramedullary infiltration (Zhu et al., 2016). EZH2 somatic mutations in AML are specific for secondary AML after an antecedent myeloid malignancy (Lindsley et al., 2015), although loss of EZH2 attenuates leukemogenicity (Sashida et al., 2014; Tanaka et al., 2012). EZH2 mutations are found with a frequency of ~2% in AML and are associated with lower blast percentage and -7/del(7q) karyotype, although they have no prognostic impact (Wang et al., 2013).

Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN), Myelodysplastic Syndrome, Myelofibrosis

EZH2 is often overexpressed in myelodysplastic syndrome (MDS) (Xu et al., 2011). Mono- and biallelic EZH2 inactivating mutations are found in 12% of myelodysplastic/myeloproliferative neoplasms and 13% of myelofibrosis (Ernst et al., 2010). They are associated with poor prognosis in myelofibrosis (Guglielmelli et al., 2011) and MDS (Bejar et al., 2011). Loss of EZH2 promotes the development of myelodysplastic syndrome in a mouse model (Khan et al., 2013; Sashida et al., 2014).

Breast Cancer

Meta-analysis shows that EZH2 overexpression is associated with estrogen receptor negativity, progesterone receptor negativity, human epidermal growth factor receptor type 2 positivity, invasive ductal cancer, Caucasian race, high histological grade, triple-negative status, and poor patient survival (Wang et al., 2015). Phosphorylation of EZH2 at residue Thr416 by CDK2 appears to play a role in malignancy of triple negative breast cancers, meaning CDK2 inhibitors could be effective in this context (Yang et al., 2015).

Prostate Cancer

High EZH2 expression is associated with an aggressive subset of prostate cancers (Varambally et al., 2002). It is correlated with a high Gleason grade, advanced tumor stage, positive nodal status, elevated PSA, early PSA recurrence, and increased cell proliferation (Melling et al., 2015). TMPRSS2-ERG rearrangements and ERG expression are also correlated (Melling et al., 2015). High EZH2 expression is linked to deletions of PTEN, 6q15, 5q21, and 3p13, particularly in ERG-negative cancers (Melling et al., 2015). High EZH2 expression is also associated with lower 5- and 10-year survival (Bachmann et al., 2006).

Endometrial Cancer

High EZH2 expression is associated with reduced progression-free and overall survival in endometrial cancer (Oki et al., 2017) and contributes to the proliferation of endometrial carcinoma (Jia et al., 2014). In vitro evidence supports inhibition of EZH2 as a viable therapeutic strategy in this cancer, possibly in combination with standard therapy (Oki et al., 2017).

Bladder Cancer

Although EZH2 provides no prognostic information, it is highly expressed in bladder cancer and higher expression is associated with higher grade invasive cancers (Warrick et al., 2016; Weikert et al., 2005).

Liver Cancer

Overexpression of EZH2 is associated with vascular invasion, histological grade, and increased cell proliferation in hepatocellular carcinoma (HCC) and combined hepatocellular and cholangiocarcinoma (Sasaki et al., 2008). The increased proliferation of HCC cells may be due to activation of Wnt/β-catenin signalling as a result of EZH2-mediated gene silencing (Cheng et al., 2011). EZH2 silences multiple tumor suppressor microRNAs in liver cancer (Au et al., 2012). The long noncoding RNA high expression in hepatocellular carcinoma (HEIH) associates with EZH2 to cause repression of EZH2 targets in liver cancer cell lines (Yang et al., 2011). Certain germline single nucleotide polymorphisms (SNPs) may confer decreased HCC risk (Yu et al., 2013).

Glioblastoma

Increased EZH2 expression correlates with higher glioma grade and confers a poor prognosis in glioblastoma patients (Zhang et al., 2015). Repression of EZH2 inhibits tumor growth in glioma cell lines (Zhang et al., 2015) and diminishes glioblastoma cancer stem cell self-renewal, possibly due to direct transcriptional regulation of MYC by EZH2 (Suvà et al., 2009). However, prolonged reduction in EZH2 expression causes cell fate switching leading to tumor progression and resistance to the drug temozolomide (de Vries et al., 2015; Fan et al., 2014). There is a positive feedback loop between EZH2 expression and β-catenin/TCF4 and STAT3 signaling in glioblastoma cells (Zhang et al., 2015). EZH2 is a direct target of microRNA-137 in glioblastoma (Sun et al., 2015).

Lung Cancer

Meta-analysis of EZH2 expression in non-small cell lung cancer (NSCLC) indicates that EZH2 overexpression is associated with poor overall survival in Asian patients, patients with lung adenocarcinoma, and stage I NSCLC patients (Wang et al., 2016). EZH2 expression increases with lung cancer development and metastasis (Wan et al., 2013) and is correlated with high promoter methylation in small cell lung cancer (Poirier et al., 2015). EZH2 inhibition in NSCLC with mutated BRG1 and EGFR sensitizes the tumor to topoisomerase II inhibition in a mouse model, while inhibiting EZH2 in BRG1 and EGFR wild-type NSCLC has the opposite effect (Fillmore et al., 2015)

Ovarian Cancer

EZH2 is overexpressed in two-thirds of ovarian carcinoma and correlates with high stage and high grade disease, and decreased overall survival (Lu et al., 2010). EZH2 is involved in angiogenesis (Lu et al., 2010) and in suppressing apoptosis (Li et al., 2010) in ovarian cancer cells. Accordingly, knockdown of EZH2 induces apoptosis and reduces invasion in these cells (Li et al., 2010). EZH2 expression, possibly mediated by microRNA-101, contributes to acquired cisplatin resistance in ovarian cancer (Hu et al., 2010; Liu et al., 2014). ARD1A mutations sensitize ovarian tumors to EZH2 inhibitors (Bitler et al., 2015).

Melanoma

High EZH2 expression in melanoma is associated with thicker primary melanomas, Clark’s level of invasion V, increased proliferation, and expression of cyclin D1 (Bachmann et al., 2006). EZH2 is able to suppress cellular senescence in melanoma cells by inhibiting p21/CDKN1A expression (Fan et al., 2011). High EZH2 expression is associated with reduced 5-year survival (Bachmann et al., 2006). Tyr646 (NM_004456.4) gain-of-function mutations have been identified in melanomas, and cell lines with these mutations form larger tumors compared to control cells in a xenograft mouse model (Barsotti et al., 2015; Hodis et al., 2012).

Gene Overview

EZH2 (Enhancer of zeste homolog 2) encodes a histone-lysine N-methyltransferase which catalyses the addition of methyl groups to lysine 27 of histone H3 (H3K27) (Kuzmichev, 2002). EZH2 and its homolog EZH1 share four domains: homolog domain I, homolog domain II, a cysteine-rich domain, and the SET (Suppressor of variegation 3-9, Enhancer-of-zeste, and Trithorax) domain (reviewed in Li and Chen, 2015). EZH1 and EZH2 function through different mechanisms (Margueron et al., 2008). EZH2 is the enzymatic subunit of the Polycomb repressive complex 2 (PRC2), which also includes the core subunits EED, SUZ12, and RbAp46/48, although interactions with other proteins also occur (Margueron and Reinberg, 2011).

PRC2 is a highly conserved chromatin modification complex involved in transcriptional silencing of target loci through EZH2-catalysed H3K27 di- and trimethylation (H3K27m2 and H3K27m3), in some contexts with the aid of downstream Polycomb repressive complex 1 (PRC1) activity (Müller et al., 2002, reviewed in Margueron and Reinberg, 2011). Major targets of PRC2-mediated methylation are key developmental regulators that are inactive in undifferentiated cells but activated during differentiation in embryogenesis, and the EZH2/PRC complex has been implicated in maintenance of pluripotency in stem cells (Lee et al., 2006). Germline mutations in EZH2 cause Weaver Syndrome, a rare congenital disorder characterised by overgrowth, advanced bone age, and distinctive skeletal and neurological abnormalities (Gibson et al., 2012).

EZH2 is important in hematopoesis where it preserves hematopoetic stem cell (HSC) potential, and overexpression of EZH2 protects against cellular senescence during serial transplantation of stem cells (Kamminga et al., 2006). In lymphopoiesis EZH2 is expressed strongly in proliferating cells including germinal center B cells, cycling T and B lymphocytes, and plasmablasts (reviewed in Good-Jacobson, 2014). Loss of EZH2 abrogates germinal center formation (Béguelin et al., 2013).

EZH2 is overexpressed in cancerous cells from many tissues where EZH2 expression would normally be low, and is universally associated with cancer progression (Bachmann et al., 2006; Bracken et al., 2003; Kleer et al., 2003; Varambally et al., 2002). Gain-of-function mutations affecting the EZH2 SET catalytic domain, which spans residues 612-727 (NM_004456.4, UniProt), have been identified primarily in non-Hodgkin lymphomas (reviewed in Kim and Roberts, 2016). These mutations reduce the affinity of EZH2 for unmethylated and monomethylated H3K27 but increase affinity for the dimethylated version (Yap et al., 2011). Wild-type and mutant EZH2 then cooperate to drive hypertrimethylation of target loci (Sneeringer et al., 2010).

EZH2 appears to function as a tumour suppressor in myeloid disorders, as inactivating mutations have been identified in these contexts (Ernst et al., 2010; Nikoloski et al., 2010). These are typically truncating mutations or missense mutations in conserved residues within the catalytic or protein-interaction domains of EZH2 (Ernst et al., 2010).

Some studies have suggested that EZH2 may also have oncogenic activating activity independent of PRC2, although this function is poorly defined. In prostate cancer this may be via a transactivator role for transcription factors including androgen receptor (Xu et al., 2012), while in breast cancer there is evidence EZH2 is involved in activating NF-κB targets and NOTCH1 while also participating in the estrogen receptor and Wnt signalling pathways (Gonzalez et al., 2014; Lee et al., 2011; Shi et al., 2007).

EZH2 can methylate non-histone targets, which may aid ubiquitin-mediated degradation of the methylated proteins, but the biological significance of this function is unclear (Lee et al., 2012).

MicroRNA-101 is a negative regulator of EZH2, and ectopic expression of miR-101 in cell lines is able to suppress cell proliferation, invasiveness, and self-renewal (Konno et al., 2014; Luo et al., 2013). AKT-mediated phosphorylation of EZH2 at Ser21 (NM_004456.4) also suppresses methylation of H3K27 by impeding EZH2 binding to histone H3 (Cha et al., 2005).

Inhibitors of EZH2 have been developed and are in various stages of trial (reviewed in Kim and Roberts, 2016). Notably, tamazetostat has shown promise in phase I clinical trials and is undergoing phase II trials (Italiano et al., 2018).

Common Alteration Types

Mutations in EZH2 are overwhelmingly Tyr646 (NM_004456.4) (sometimes reported in the literature as Tyr641) missense gain-of-function mutations. Lys634, Val637, Ala677, Val679, Ala682, Ala687 and Ala692 (all NM_004456.4) have also been reported as sites of missense gain-of-function mutations. The COSMIC database of somatic variants indicates Arg690 and Asp185 (NM_004456.4) mutations are also somewhat common (COSMIC). No clear pattern of other mutations is evident.

Copy Number Loss Copy Number Gain LOH Loss-of-Function Mutation Gain-of-Function Mutation Translocation/Fusion
EXAMPLE: X EXAMPLE: X EXAMPLE: X EXAMPLE: X EXAMPLE: X EXAMPLE: X

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External Links

EZH2 by Atlas of Genetics and Cytogenetics in Oncology and Haematology - detailed gene information

EZH2 by COSMIC - sequence information, expression, catalogue of mutations

EZH2 by CIViC - general knowledge and evidence-based variant specific information

EZH2 by St. Jude ProteinPaint mutational landscape and matched expression data.

EZH2 by Precision Medicine Knowledgebase (Weill Cornell) - manually vetted interpretations of variants and CNVs

EZH2 by Cancer Index - gene, pathway, publication information matched to cancer type

EZH2 by OncoKB - mutational landscape, mutation effect, variant classification

EZH2 by My Cancer Genome - brief gene overview

EZH2 by UniProt - protein and molecular structure and function

EZH2 by Pfam - gene and protein structure and function information

EZH2 by GeneCards - general gene information and summaries

References

  • Abdalkader, L., Oka, T., Takata, K., Sato, H., Murakami, I., Otte, A.P., and Yoshino, T. (2016). Aberrant differential expression of EZH1 and EZH2 in Polycomb repressive complex 2 among B- and T/NK-cell neoplasms. Pathology (Phila.) 48, 467–482. PMID: 27311868
  • Au, S.L., Wong, C.C., Lee, J.M., Fan, D.N., Tsang, F.H., Ng, I.O., and Wong, C.M. (2012). Enhancer of zeste homolog 2 epigenetically silences multiple tumor suppressor microRNAs to promote liver cancer metastasis. Hepatol. Baltim. Md 56, 622–631. PMID: 22370893
  • Bachmann, I.M., Halvorsen, O.J., Collett, K., Stefansson, I.M., Straume, O., Haukaas, S.A., Salvesen, H.B., Otte, A.P., and Akslen, L.A. (2006). EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 24, 268–273. PMID: 16330673
  • Barsotti, A.M., Ryskin, M., Zhong, W., Zhang, W.G., Giannakou, A., Loreth, C., Diesl, V., Follettie, M., Golas, J., Lee, M., et al. (2015). Epigenetic reprogramming by tumor-derived EZH2 gain-of-function mutations promotes aggressive 3D cell morphologies and enhances melanoma tumor growth. Oncotarget 6, 2928–2938. PMID: 25671303
  • Béguelin, W., Popovic, R., Teater, M., Jiang, Y., Bunting, K.L., Rosen, M., Shen, H., Yang, S.N., Wang, L., Ezponda, T., et al. (2013). EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell 23, 677–692. PMID: 23680150
  • Bejar, R., Stevenson, K., Abdel-Wahab, O., Galili, N., Nilsson, B., Garcia-Manero, G., Kantarjian, H., Raza, A., Levine, R.L., Neuberg, D., et al. (2011). Clinical effect of point mutations in myelodysplastic syndromes. N. Engl. J. Med. 364, 2496–2506. PMID: 21714648
  • Bitler, B.G., Aird, K.M., Garipov, A., Li, H., Amatangelo, M., Kossenkov, A.V., Schultz, D.C., Liu, Q., Shih, I.M., Conejo-Garcia, J.R., et al. (2015). Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat. Med. 21, 231–238. PMID: 25686104
  • Bödör, C., Grossmann, V., Popov, N., Okosun, J., O’Riain, C., Tan, K., Marzec, J., Araf, S., Wang, J., Lee, A.M., et al. (2013). EZH2 mutations are frequent and represent an early event in follicular lymphoma. Blood 122, 3165–3168. PMID: 24052547
  • Bracken, A.P., Pasini, D., Capra, M., Prosperini, E., Colli, E., and Helin, K. (2003). EZH2 is downstream of the pRB‐E2F pathway, essential for proliferation and amplified in cancer. EMBO J. 22, 5323–5335. PMID: 14532106
  • Cha, T.-L., Zhou, B.P., Xia, W., Wu, Y., Yang, C.-C., Chen, C.-T., Ping, B., Otte, A.P., and Hung, M.-C. (2005). Akt-mediated phosphorylation of EZH2 suppresses methylation of lysine 27 in histone H3. Science 310, 306–310. PMID: 16224021
  • Cheng, A.S.L., Lau, S.S., Chen, Y., Kondo, Y., Li, M.S., Feng, H., Ching, A.K., Cheung, K.F., Wong, H.K., Tong, J.H., et al. (2011). EZH2-Mediated Concordant Repression of Wnt Antagonists Promotes β-Catenin–Dependent Hepatocarcinogenesis. Cancer Res. 71, 4028–4039. PMID: 21512140
  • de Vries, N.A., Hulsman, D., Akhtar, W., de Jong, J., Miles, D.C., Blom, M., van Tellingen, O., Jonkers, J., and van Lohuizen, M. (2015). Prolonged Ezh2 Depletion in Glioblastoma Causes a Robust Switch in Cell Fate Resulting in Tumor Progression. Cell Rep. 10, 383–397. PMID: 25600873
  • Ernst, T., Chase, A.J., Score, J., Hidalgo-Curtis, C.E., Bryant, C., Jones, A.V., Waghorn, K., Zoi, K., Ross, F.M., Reiter, A., et al. (2010). Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat. Genet. 42, 722–726. PMID: 20601953
  • Fan, T., Jiang, S., Chung, N., Alikhan, A., Ni, C., Lee, C.C.R., and Hornyak, T.J. (2011). EZH2-dependent suppression of a cellular senescence phenotype in melanoma cells by inhibition of p21/CDKN1A expression. Mol. Cancer Res. MCR 9, 418–429. PMID: 21383005
  • Fan, T.Y., Wang, H., Xiang, P., Liu, Y.W., Li, H.Z., Lei, B.X., Yu, M., and Qi, S.T. (2014). Inhibition of EZH2 reverses chemotherapeutic drug TMZ chemosensitivity in glioblastoma. Int. J. Clin. Exp. Pathol. 7, 6662–6670. PMID: 25400745
  • Fillmore, C.M., Xu, C., Desai, P.T., Berry, J.M., Rowbotham, S.P., Lin, Y.J., Zhang, H., Marquez, V.E., Hammerman, P.S., Wong, K.-K., et al. (2015). EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumors to TopoII inhibitors. Nature 520, 239–242. PMID: 25629630
  • Gibson, W.T., Hood, R.L., Zhan, S.H., Bulman, D.E., Fejes, A.P., Moore, R., Mungall, A.J., Eydoux, P., Babul-Hirji, R., An, J., et al. (2012). Mutations in EZH2 Cause Weaver Syndrome. Am. J. Hum. Genet. 90, 110–118. PMID: 22177091
  • Gonzalez, M.E., Moore, H.M., Li, X., Toy, K.A., Huang, W., Sabel, M.S., Kidwell, K.M., and Kleer, C.G. (2014). EZH2 expands breast stem cells through activation of NOTCH1 signaling. Proc. Natl. Acad. Sci. U. S. A. 111, 3098–3103. PMID: 24516139
  • Good-Jacobson, K.L. (2014). Regulation of Germinal Center, B-Cell Memory, and Plasma Cell Formation by Histone Modifiers. Front. Immunol. 5. PMID: 25477884
  • Grubach, L., Juhl-Christensen, C., Rethmeier, A., Olesen, L.H., Aggerholm, A., Hokland, P., and Ostergaard, M. (2008). Gene expression profiling of Polycomb, Hox and Meis genes in patients with acute myeloid leukaemia. Eur. J. Haematol. 81, 112–122. PMID: 18410541
  • Guglielmelli, P., Biamonte, F., Score, J., Hidalgo-Curtis, C., Cervantes, F., Maffioli, M., Fanelli, T., Ernst, T., Winkelman, N., Jones, A.V., et al. (2011). EZH2 mutational status predicts poor survival in myelofibrosis. Blood 118, 5227–5234. PMID: 21921040
  • Hodis, E., Watson, I.R., Kryukov, G.V., Arold, S.T., Imielinski, M., Theurillat, J.P., Nickerson, E., Auclair, D., Li, L., Place, C., et al. (2012). A Landscape of Driver Mutations in Melanoma. Cell 150, 251–263. PMID: 22817889
  • Hu, S., Yu, L., Li, Z., Shen, Y., Wang, J., Cai, J., Xiao, L., and Wang, Z. (2010). Overexpression of EZH2 contributes to acquired cisplatin resistance in ovarian cancer cells in vitro and in vivo. Cancer Biol. Ther. 10, 788–795. PMID: 20686362
  • Italiano, A., Soria, J.C., Toulmonde, M., Michot, J.-M., Lucchesi, C., Varga, A., Coindre, J.-M., Blakemore, S.J., Clawson, A., Suttle, B., et al. (2018). Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study. Lancet Oncol. 19, 649–659. PMID: 29650362
  • Jia, N., Li, Q., Tao, X., Wang, J., Hua, K., and Feng, W. (2014). Enhancer of zeste homolog 2 is involved in the proliferation of endometrial carcinoma. Oncol. Lett. 8, 2049–2054. PMID: 25295088
  • Kamminga, L.M., Bystrykh, L.V., de Boer, A., Houwer, S., Douma, J., Weersing, E., Dontje, B., and de Haan, G. (2006). The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion. Blood 107, 2170–2179. PMID: 16293602
  • Khan, S.N., Jankowska, A.M., Mahfouz, R., Dunbar, A.J., Sugimoto, Y., Hosono, N., Hu, Z., Cheriyath, V., Vatolin, S., Przychodzen, B., et al. (2013). Multiple mechanisms deregulate EZH2 and histone H3 lysine 27 epigenetic changes in myeloid malignancies. Leukemia 27, 1301–1309. PMID: 23486531
  • Kim, K.H., and Roberts, C.W.M. (2016). Targeting EZH2 in cancer. Nat. Med. 22, 128–134. PMID: 26845405
  • Kim, S.H., Yang, W.I., Min, Y.H., Ko, Y.H., and Yoon, S.O. (2016). The role of the polycomb repressive complex pathway in T and NK cell lymphoma: biological and prognostic implications. Tumour Biol. J. Int. Soc. Oncodevelopmental Biol. Med. 37, 2037–2047. PMID: 26337274
  • Kleer, C.G., Cao, Q., Varambally, S., Shen, R., Ota, I., Tomlins, S.A., Ghosh, D., Sewalt, R.G.A.B., Otte, A.P., Hayes, D.F., et al. (2003). EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc. Natl. Acad. Sci. U. S. A. 100, 11606–11611. PMID: 14500907
  • Konno, Y., Dong, P., Xiong, Y., Suzuki, F., Lu, J., Cai, M., Watari, H., Mitamura, T., Hosaka, M., Hanley, S.J.B., et al. (2014). MicroRNA-101 targets EZH2, MCL-1 and FOS to suppress proliferation, invasion and stem cell-like phenotype of aggressive endometrial cancer cells. Oncotarget 5, 6049–6062. PMID: 25153722
  • Kuzmichev, A. (2002). Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev. 16, 2893–2905. PMID: 12435631
  • Lee, J.M., Lee, J.S., Kim, H., Kim, K., Park, H., Kim, J.Y., Lee, S.H., Kim, I.S., Kim, J., Lee, M., et al. (2012). EZH2 generates a methyl degron that is recognized by the DCAF1/DDB1/CUL4 E3 ubiquitin ligase complex. Mol. Cell 48, 572–586. PMID: 23063525
  • Lee, S.T., Li, Z., Wu, Z., Aau, M., Guan, P., Karuturi, R.K.M., Liou, Y.C., and Yu, Q. (2011). Context-specific regulation of NF-κB target gene expression by EZH2 in breast cancers. Mol. Cell 43, 798–810. PMID: 21884980
  • Lee, T.I., Jenner, R.G., Boyer, L.A., Guenther, M.G., Levine, S.S., Kumar, R.M., Chevalier, B., Johnstone, S.E., Cole, M.F., Isono, K., et al. (2006). Control of Developmental Regulators by Polycomb in Human Embryonic Stem Cells. Cell 125, 301–313. PMID: 16630818
  • Li, C.H., and Chen, Y. (2015). Targeting EZH2 for Cancer Therapy: Progress and Perspective. Curr. Protein Pept. Sci. 16, 559–570. PMID: 25854924
  • Li, H., Cai, Q., Godwin, A.K., and Zhang, R. (2010). Enhancer of zeste homolog 2 promotes the proliferation and invasion of epithelial ovarian cancer cells. Mol. Cancer Res. MCR 8, 1610–1618. PMID: 21115743
  • Lindsley, R.C., Mar, B.G., Mazzola, E., Grauman, P.V., Shareef, S., Allen, S.L., Pigneux, A., Wetzler, M., Stuart, R.K., Erba, H.P., et al. (2015). Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood 125, 1367–1376. PMID: 25550361
  • Liu, L., Guo, J., Yu, L., Cai, J., Gui, T., Tang, H., Song, L., Wang, J., Han, F., Yang, C., et al. (2014). miR-101 regulates expression of EZH2 and contributes to progression of and cisplatin resistance in epithelial ovarian cancer. Tumour Biol. J. Int. Soc. Oncodevelopmental Biol. Med. 35, 12619–12626. PMID: 25260883
  • Lu, C., Han, H.D., Mangala, L.S., Ali-Fehmi, R., Newton, C.S., Ozbun, L., Armaiz-Pena, G.N., Hu, W., Stone, R.L., Munkarah, A., et al. (2010). Regulation of Tumor Angiogenesis by EZH2. Cancer Cell 18, 185–197. PMID: 20708159
  • Luo, C., Merz, P.R., Chen, Y., Dickes, E., Pscherer, A., Schadendorf, D., and Eichmüller, S.B. (2013). MiR-101 inhibits melanoma cell invasion and proliferation by targeting MITF and EZH2. Cancer Lett. 341, 240–247. PMID: 23962556
  • Majer, C.R., Jin, L., Scott, M.P., Knutson, S.K., Kuntz, K.W., Keilhack, H., Smith, J.J., Moyer, M.P., Richon, V.M., Copeland, R.A., et al. (2012). A687V EZH2 is a gain-of-function mutation found in lymphoma patients. FEBS Lett. 586, 3448–3451. PMID: 22850114
  • Margueron, R., and Reinberg, D. (2011). The Polycomb complex PRC2 and its mark in life. Nature 469, 343–349. PMID: 21248841
  • Margueron, R., Li, G., Sarma, K., Blais, A., Zavadil, J., Woodcock, C.L., Dynlacht, B.D., and Reinberg, D. (2008). Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms. Mol. Cell 32, 503–518. PMID: 19026781
  • McCabe, M.T., Graves, A.P., Ganji, G., Diaz, E., Halsey, W.S., Jiang, Y., Smitheman, K.N., Ott, H.M., Pappalardi, M.B., Allen, K.E., et al. (2012). Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proc. Natl. Acad. Sci. U. S. A. 109, 2989–2994. PMID: 22323599
  • Melling, N., Thomsen, E., Tsourlakis, M.C., Kluth, M., Hube-Magg, C., Minner, S., Koop, C., Graefen, M., Heinzer, H., Wittmer, C., et al. (2015). Overexpression of enhancer of zeste homolog 2 (EZH2) characterizes an aggressive subset of prostate cancers and predicts patient prognosis independently from pre- and postoperatively assessed clinicopathological parameters. Carcinogenesis 36, 1333–1340. PMID: 26392259
  • Morin, R.D., Johnson, N.A., Severson, T.M., Mungall, A.J., An, J., Goya, R., Paul, J.E., Boyle, M., Woolcock, B.W., Kuchenbauer, F., et al. (2010). Somatic mutation of EZH2 (Y641) in Follicular and Diffuse Large B-cell Lymphomas of Germinal Center Origin. Nat. Genet. 42, 181–185. PMID: 20081860
  • Müller, J., Hart, C.M., Francis, N.J., Vargas, M.L., Sengupta, A., Wild, B., Miller, E.L., O’Connor, M.B., Kingston, R.E., and Simon, J.A. (2002). Histone Methyltransferase Activity of a Drosophila Polycomb Group Repressor Complex. Cell 111, 197–208. PMID: 12408864
  • Nikoloski, G., Langemeijer, S.M.C., Kuiper, R.P., Knops, R., Massop, M., Tönnissen, E.R.L.T.M., van der Heijden, A., Scheele, T.N., Vandenberghe, P., de Witte, T., et al. (2010). Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat. Genet. 42, 665–667. PMID: 20601954
  • Ntziachristos, P., Tsirigos, A., Van Vlierberghe, P., Nedjic, J., Trimarchi, T., Flaherty, M.S., Ferres-Marco, D., da Ros, V., Tang, Z., Siegle, J., et al. (2012). Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nat. Med. 18, 298–301. PMID: 22237151
  • Oki, S., Sone, K., Oda, K., Hamamoto, R., Ikemura, M., Maeda, D., Takeuchi, M., Tanikawa, M., Mori-Uchino, M., Nagasaka, K., et al. (2017). Oncogenic histone methyltransferase EZH2: A novel prognostic marker with therapeutic potential in endometrial cancer. Oncotarget 8. PMID: 28418882
  • Poirier, J.T., Gardner, E.E., Connis, N., Moreira, A.L., de Stanchina, E., Hann, C.L., and Rudin, C.M. (2015). DNA methylation in small cell lung cancer defines distinct disease subtypes and correlates with high expression of EZH2. Oncogene 34, 5869–5878. PMID: 25746006
  • Reddy, A., Zhang, J., Davis, N.S., Moffitt, A.B., Love, C.L., Waldrop, A., Leppa, S., Pasanen, A., Meriranta, L., Karjalainen-Lindsberg, M.-L., et al. (2017). Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma. Cell 171, 481-494.e15. PMID: 28985567
  • Ryan, R.J.H., Nitta, M., Borger, D., Zukerberg, L.R., Ferry, J.A., Harris, N.L., Iafrate, A.J., Bernstein, B.E., Sohani, A.R., and Le, L.P. (2011). EZH2 codon 641 mutations are common in BCL2-rearranged germinal center B cell lymphomas. PloS One 6, e28585. PMID: 22194861
  • Sasaki, M., Ikeda, H., Itatsu, K., Yamaguchi, J., Sawada, S., Minato, H., Ohta, T., and Nakanuma, Y. (2008). The overexpression of polycomb group proteins Bmi1 and EZH2 is associated with the progression and aggressive biological behavior of hepatocellular carcinoma. Lab. Invest. 88, 873–882. PMID: 18591938
  • Sashida, G., Harada, H., Matsui, H., Oshima, M., Yui, M., Harada, Y., Tanaka, S., Mochizuki-Kashio, M., Wang, C., Saraya, A., et al. (2014). Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation. Nat. Commun. 5, 4177. PMID: 24953053
  • Shi, B., Liang, J., Yang, X., Wang, Y., Zhao, Y., Wu, H., Sun, L., Zhang, Y., Chen, Y., Li, R., et al. (2007). Integration of estrogen and Wnt signaling circuits by the polycomb group protein EZH2 in breast cancer cells. Mol. Cell. Biol. 27, 5105–5119. PMID: 17502350
  • Sneeringer, C.J., Scott, M.P., Kuntz, K.W., Knutson, S.K., Pollock, R.M., Richon, V.M., and Copeland, R.A. (2010). Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc. Natl. Acad. Sci. U. S. A. 107, 20980–20985. PMID: 21078963
  • Sun, J., Zheng, G., Gu, Z., and Guo, Z. (2015). MiR-137 inhibits proliferation and angiogenesis of human glioblastoma cells by targeting EZH2. J. Neurooncol. 122, 481–489. PMID: 25939439
  • Suvà, M.L., Riggi, N., Janiszewska, M., Radovanovic, I., Provero, P., Stehle, J.C., Baumer, K., Bitoux, M.A.L., Marino, D., Cironi, L., et al. (2009). EZH2 Is Essential for Glioblastoma Cancer Stem Cell Maintenance. Cancer Res. 69, 9211–9218. PMID: 19934320
  • Tanaka, S., Miyagi, S., Sashida, G., Chiba, T., Yuan, J., Mochizuki-Kashio, M., Suzuki, Y., Sugano, S., Nakaseko, C., Yokote, K., et al. (2012). Ezh2 augments leukemogenicity by reinforcing differentiation blockage in acute myeloid leukemia. Blood 120, 1107–1117. PMID: 22677129
  • Varambally, S., Dhanasekaran, S.M., Zhou, M., Barrette, T.R., Kumar-Sinha, C., Sanda, M.G., Ghosh, D., Pienta, K.J., Sewalt, R.G.A.B., Otte, A.P., et al. (2002). The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629. PMID: 12374981
  • Wan, L., Li, X., Shen, H., and Bai, X. (2013). Quantitative analysis of EZH2 expression and its correlations with lung cancer patients’ clinical pathological characteristics. Clin. Transl. Oncol. Off. Publ. Fed. Span. Oncol. Soc. Natl. Cancer Inst. Mex. 15, 132–138. PMID: 22855181
  • Wang, X., Dai, H., Wang, Q., Wang, Q., Xu, Y., Wang, Y., Sun, A., Ruan, J., Chen, S., and Wu, D. (2013). EZH2 Mutations Are Related to Low Blast Percentage in Bone Marrow and -7/del(7q) in De Novo Acute Myeloid Leukemia. PLoS ONE 8. PMID: 23613835
  • Wang, X., Hu, B., Shen, H., Zhou, H., Xue, X., Chen, Y., Chen, S., Han, Y., Yuan, B., Zhao, H., et al. (2015). Clinical and prognostic relevance of EZH2 in breast cancer: A meta-analysis. Biomed. Pharmacother. Biomedecine Pharmacother. 75, 218–225. PMID: 26271144
  • Wang, X., Zhao, H., Lv, L., Bao, L., Wang, X., and Han, S. (2016). Prognostic Significance of EZH2 Expression in Non-Small Cell Lung Cancer: A Meta-analysis. Sci. Rep. 6. PMID: 26754405
  • Warrick, J.I., Raman, J.D., Kaag, M., Bruggeman, T., Cates, J., Clark, P., and DeGraff, D.J. (2016). Enhancer of zeste homolog 2 (EZH2) expression in bladder cancer. Urol. Oncol. 34, 258.e1-6. PMID: 26976725
  • Weikert, S., Christoph, F., Köllermann, J., Müller, M., Schrader, M., Miller, K., and Krause, H. (2005). Expression levels of the EZH2 polycomb transcriptional repressor correlate with aggressiveness and invasive potential of bladder carcinomas. Int. J. Mol. Med. 16, 349–353. PMID: 16012774
  • Xu, F., Li, X., Wu, L., Zhang, Q., Yang, R., Yang, Y., Zhang, Z., He, Q., and Chang, C. (2011). Overexpression of the EZH2, RING1 and BMI1 genes is common in myelodysplastic syndromes: relation to adverse epigenetic alteration and poor prognostic scoring. Ann. Hematol. 90, 643–653. PMID: 21125401
  • Xu, K., Wu, Z.J., Groner, A.C., He, H.H., Cai, C., Lis, R.T., Wu, X., Stack, E.C., Loda, M., Liu, T., et al. (2012). EZH2 Oncogenic Activity in Castration Resistant Prostate Cancer Cells is Polycomb-Independent. Science 338, 1465–1469. PMID: 23239736
  • Yan, J., Ng, S.B., Tay, J.L.S., Lin, B., Koh, T.L., Tan, J., Selvarajan, V., Liu, S.C., Bi, C., Wang, S., et al. (2013). EZH2 overexpression in natural killer/T-cell lymphoma confers growth advantage independently of histone methyltransferase activity. Blood 121, 4512–4520. PMID: 23529930
  • Yang, C.C., LaBaff, A., Wei, Y., Nie, L., Xia, W., Huo, L., Yamaguchi, H., Hsu, Y.H., Hsu, J.L., Liu, D., et al. (2015). Phosphorylation of EZH2 at T416 by CDK2 contributes to the malignancy of triple negative breast cancers. Am. J. Transl. Res. 7, 1009–1020. PMID: 26279746 PMID: 26279746
  • Yang, F., Zhang, L., Huo, X., Yuan, J., Xu, D., Yuan, S., Zhu, N., Zhou, W., Yang, G., Wang, Y., et al. (2011). Long noncoding RNA high expression in hepatocellular carcinoma facilitates tumor growth through enhancer of zeste homolog 2 in humans. Hepatol. Baltim. Md 54, 1679–1689. PMID: 21769904
  • Yap, D.B., Chu, J., Berg, T., Schapira, M., Cheng, S.W.G., Moradian, A., Morin, R.D., Mungall, A.J., Meissner, B., Boyle, M., et al. (2011). Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood 117, 2451–2459. PMID: 21190999
  • Yu, Y.L., Su, K.J., Hsieh, Y.H., Lee, H.L., Chen, T.Y., Hsiao, P.C., and Yang, S.F. (2013). Effects of EZH2 Polymorphisms on Susceptibility to and Pathological Development of Hepatocellular Carcinoma. PLoS ONE 8(9), e74870. PMID: 24040354
  • Zhang, J., Chen, L., Han, L., Shi, Z., Zhang, J., Pu, P., and Kang, C. (2015). EZH2 is a negative prognostic factor and exhibits pro-oncogenic activity in glioblastoma. Cancer Lett. 356, 929–936. PMID: 25444902
  • Zhu, Q., Zhang, L., Li, X., Chen, F., Jiang, L., Yu, G., Wang, Z., Yin, C., Jiang, X., Zhong, Q., et al. (2016). Higher EZH2 expression is associated with extramedullary infiltration in acute myeloid leukemia. Tumour Biol. J. Int. Soc. Oncodevelopmental Biol. Med. 37, 11409–11420. PMID: 27000755

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