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Targeting EZH2 in cancer therapy

Yamagishi, Makoto; Uchimaru, Kaoru

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doi: 10.1097/CCO.0000000000000390
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Cell fate decisions depend on gene expression patterns that are dynamically defined by the transcriptome. Therefore, dysregulation of transcription is a determinant of cancer phenotype [1]. Epigenetic regulation of transcription is a series of dynamic and plastic processes that is coordinated by complicated machinery [2–4]. In particular, euchromatic regions are regulated by a number of elements comprising epigenetic writers, such as the polycomb and trithorax groups [5–7], and chromatin remodeling factors, such as the SWI/SNF complex [8,9]. Abnormal chromatin regulation is frequently observed in all cancers, supporting the concept that, in addition to genetic legions, epigenetic disorder is a fundamental hallmark of cancer.

EZH2 is a pleiotropically acting molecule; its primary conserved function is in epigenetic gene suppression as an essential component of polycomb repressive complex 2 (PRC2) [6]. EZH2 is one of the two essential catalytic enzymes for the methylation of histone H3 lysine 27 (H3K27) in mammalian cells. Accumulated evidence suggests that EZH2 is deeply involved in aberrant transcriptome in cancer cells [10]. Indeed, EZH2 and the product of its enzymatic action H3K27me3 have been associated with poor prognosis in a variety of human malignancies. EZH2 amplification and functional alteration are frequently observed in a majority of cancers. Several studies have provided evidence that inhibiting EZH2 has great prospects/potential in treating different cancer types.

Potential difficulty for targeting EZH2 is recognized because the dynamic regulation of PRC2 occurs in all cellular processes, including normal cell development, differentiation, and reproduction. This comprehensive view is encouraging worldwide researchers and clinicians by analyzing the complicated mechanisms of chromatin regulation, defining cancer types that are really addicted to aberrant EZH2, and developing ways for appropriate EZH2 manipulation to achieve precision therapy. Herein, we introduce the recent outstanding progress, particularly pertaining to the modes of action of EZH2 as a master regulator of chromatin, and provide molecular-based evidence for targeting EZH2. We discuss the importance and druggability of EZH2 in cancer biology by reviewing the enhanced development of small molecules that effectively inhibit the enzymatic activity of EZH2/PRC2, which are translated into early-phase clinical trials. 

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The complexity of EZH2 regulation through multiple mechanisms strongly suggests that EZH2 plays a pivotal role in various types of cells with diverse functions. Somatic mutations in the EZH2 gene are observed in specific cancer types. Some populations of B-cell lymphomas [diffuse large B-cell lymphoma (DLBCL) 22%; follicular lymphoma 7–12%] show heterozygous somatic point mutations in EZH2, mainly Y641, within the C-terminal catalytic SET domain [11,12]. Functional analysis has demonstrated that mutated EZH2 has little function on unmodified histone H3 but preferentially methylates dimethyl H3K27 [13]. Monoallelic mutation results in the expression of wild-type and mutated EZH2, leading to the accumulation of the suppressive mark H3K27me3, which causes the dysregulation of transcriptome in lymphoma cells [14,15▪].

In contrast, EZH2 inactivating deletions, frameshift, and nonsense and missense mutations have been identified in myelodysplastic syndromes (MDSs 2.5%), myeloproliferative neoplasms (MPNs 3–13%), MDS-MPN overlap disorders (8–12%) [16,17], and T-cell acute lymphocytic leukemia (T-ALL) (18–25%) [18,19]. Although the functional involvement of EZH2 loss in premature hematological malignancies has not been fully investigated, context and cell-of-origin-dependent differential roles of EZH2 in cancer development are implicated.


The first report implicating the role of EZH2 in cancer biology is from a prostate cancer study. Increased levels of EZH2 and H3K27me3 are correlated with poor outcomes in metastatic prostate cancer [20]. Furthermore, solid cancers, including breast, endometrial, ovarian, melanoma, bladder, glioblastoma, kidney, colorectal, and lung cancers, and hematological malignancies, such as T-cell and B-cell lymphomas, show EZH2 overexpression and elevated H3K27me3 [3,10]. These reproducible observations indicate that the function of PRC2 is well correlated with the transcriptional activity of the EZH2 gene.

Detailed promoter sequence analyses have revealed the transcription factors that affect the EZH2 gene, which include pRB-E2F [21], MEK-ERK-ELK1 [22], KRAS mutations and downstream ERK or Akt [23], hypoxia-induced HIF-1α [24], and NF-κB [25▪▪] (Fig. 1).

Oncogenic process with EZH2. Several oncogenic hits promote EZH2 expression and enzymatic activity. The activated EZH2 mainly acts in suppression of the numerous target genes as a key PRC2 component. Consequently, EZH2 establishes cancer transcriptome by suppression of gene regulators, such as microRNA, transcription factors and epigenetic regulators, and activation of signaling pathways. PRC2, polycomb repressive complex 2.

We recently demonstrated that direct binding of the NF-κB components to the EZH2 gene promoter activates transcription in human T-cell leukemia virus type I (HTLV-1)-infected adult T-cell leukemia–lymphoma (ATL) cells [25▪▪]. Therefore, cancer-related oncogenic signaling pathways are closely associated with EZH2 transcription, suggesting that EZH2 expression is a clinical biomarker for disease progression and cancer development. In addition, functional linkage between signaling pathways and EZH2-dependent epigenetic abnormality has been demonstrated [26]. For example, multistep lymphomagenesis has been implicated in HTLV-1-infected cells. A cell-based study revealed that EZH2 mRNA is gradually upregulated from early stage and contributes to lymphoma development [25▪▪].

MicroRNA-dependent posttranscriptional regulation of EZH2 is also implicated in several cancers. Some microRNAs specifically bind the EZH2 mRNA 3′UTR and modulate its expression via mRNA stability and translation regulation. In particular, miR-26a and miR-101 have been well demonstrated as negative regulators of EZH2. In specific cancer types, the downregulation of these microRNA leads to EZH2 overexpression and subsequent H3K27me3 accumulation [27–29].

Protein modification of EZH2 affects enzymatic function. Akt-mediated phosphorylation at Ser21 of EZH2 suppresses methylation of H3K27 [30]. Genome-wide analysis of EZH2 distribution revealed an H3K27me3-independent function of EZH2. The phosphorylated EZH2 is involved in the development and progression of castration-resistant prostate cancer by promoting the expression of androgen receptor target genes [31]. The phosphorylation of EZH2 also activates STAT3 signaling via STAT3 methylation and promotes glioblastoma tumorigenesis [32]. In addition, phosphorylation of EZH2 at Thr350 by CDK1/2 is important for the recruitment of EZH2 and maintenance of H3K27me3 levels at EZH2 target loci [33]. Phosphorylation of EZH2 Thr487 induced by CDK1 not only inhibits binding of EZH2 to its target region, but also inhibits methyltransferase activity [34]. Collectively, regulation of EZH2 at the posttranslational level may be of particular importance with regard to its activity.


Qualitative and quantitative hyperactivation of EZH2 promotes tumorigenesis by acting as a core component of PRC2 and by altering the expression of many functional genes that participate in lineage specification, cell cycle regulation, and DNA repair. Transcriptome/epigenome analyses of cells with EZH2 manipulations have identified numerous genes in each cancer type. Some common EZH2 targets have been identified by cross-sectional comparison. For example, EZH2-dependent repression of p16/CDKN2A results in cell cycle progression observed in multiple cancers. However, thousands of EZH2/PRC2 targets vary depending on the cell type [5,35]. Given that epigenetic landscapes are distinguished by their cell of origin and developmental history of the tumor, the consequences of cell fate control by EZH2 are likely to be highly cell-type specific.

In addition to the suppression of tumor suppressor genes, other EZH2 targets create secondary gene regulatory network. H3K27me3 accumulation is frequently observed in loci encoding other transcription factors and epigenetic modifiers, such as the histone lysine demethylase (KDM) family [25▪▪]. Furthermore, the NF-κB pathway is downstream of EZH2. In ATL cells, activated PRC2 induces H3K27me3 accumulation at the locus that encodes miR-31, which is a negative regulator of NF-κB-inducing kinase [26]. The epigenetically activated NF-κB pathway can be inhibited by EZH2 inhibition. A complete loss of miR-31 is observed in all ATL patients (52 of 52, 100%), suggesting that this is an essential step for ATL development [36]. In addition, the functional association between EZH2 and NF-κB is implicated in metastatic cancers through the regulation of miR-31 [26,37], DAB2IP[38], and physical association between EZH2 and RelA/RelB [39].

MicroRNAs are important downstream targets of EZH2. MicroRNA dysfunction is one of the molecular hallmarks of cancers [40,41]. In some malignancies, EZH2 epigenetically silences several microRNAs that act as tumor suppressors, including miR-31 [26,37,42], miR-200b/c, and miR-203 [43,44].

These executive molecular processes initiated by EZH2 appear to be the fundamental characteristics of each cancer, suggesting that targeting EZH2 is one of the extrinsic ways for modulation of the cancer transcriptome (Fig. 1).


EZH2 level well correlates with PRC2 function and thus cellular H3K27me3 level. However, H3K27me3 level cannot simply explain the cancer-specific epigenome and subsequent transcription regulatory network. Recent high-resolution chromatin data have clearly indicated that complicated epigenetic reprogramming is induced in cancers, highlighting the role of multiple epigenetic factors in the development and progression of human cancers. Recent comprehensive studies have proposed conceptual advanced, orchestrated regulation of chromatin by EZH2 and other epigenetic factors.

The BRG1-associated or BRM-associated factor (BAF or SWI/SNF) chromatin remodeling complex comprises multiple protein subunits. Members of the BAF complex are classically identified as tumor suppressors, and BAF genes are recurrently mutated in up to 20% of all human cancers [8,9,45–47]. Genetic interactions regarding synthetic lethality by targeting EZH2 have been implicated in BAF-mutated cancer types. The pioneer study of EZH2 genetic interaction showed that the loss of the SNF5 (SMARCB1) tumor suppressor leads to EZH2 upregulation and broad accumulation of H3K27me3 [48]. The antagonizing functions between SNF5 and EZH2 are implicated in the regulation of stem cell-associated programs and tumor formation driven by the loss of SNF5. EZH2 inhibition shows early signs of promise in clinical trials for SMARCB1-deficient malignant rhabdoid tumors, which is an extremely aggressive childhood cancer (

The antagonistic relationship is evolutionarily conserved. Recently, the molecular mechanism of dynamic chromatin regulation within a few minutes has been reported. The BAF complex directly evicts PRC1 and PRC2 [49▪]. Phenotypic and molecular analyses have suggested that EZH2 is a strong candidate for the synthetic lethality of cancers harboring epigenetic disorders. Recent studies support this concept. Synthetic lethality by targeting EZH2 activity in ARID1A-mutated cancers has been previously reported [50▪▪]. ARID1A is mutated in more than 50% of ovarian clear-cell carcinomas [46,51,52]. In addition, the SWI/SNF subunits PBRM1 and BRG1 have been reported to be synthetically lethal along with EZH2 [53▪,54▪] (Fig. 2).

Potential eligibility for targeting EZH2. Genome-wide epigenetic pattern (epigenome) is established by functional balance between polycomb and SWI/SNF, KDM6A, or BAP1. The suggested eligibility for targeting EZH2 is gain of EZH2/PRC2 function (upregulation or mutation) or loss of function in the antagonistic molecules.

Similar PRC2 addiction has been observed in cancers with mutated in KDM6A and BAP1 genes. The tumor suppressor BAP1 interacts to form a polycomb deubiquitinase complex that removes H2AK119ub [55]. The loss of Bap1 results in H3K27me3 accumulation and strong repression of PRC2 targets. Conditional deletion of Bap1 and Ezh2 in vivo abrogates the myeloid progenitor expansion induced by the loss of Bap1 alone. Indeed, mesothelioma cells that lack BAP1 are sensitive to EZH2 inhibitors [56▪]. In bladder cancer, the H3K27 demethylase KDM6A is frequently mutated [46,57]. Cells with the loss of KDM6A are vulnerable to EZH2. Inhibition of EZH2 delays tumor onset in KDM6A-null cells and causes regression of KDM6A-null bladder tumors in both patient-derived and cell line xenograft models [58▪].

Histone H3 mutation (lysine 27 is substituted with methionine H3K27 M) is frequently observed in diffuse intrinsic pontine glioma (DIPG) [59] and leads to the global loss of H3K27me3 [60,61]. The retained H3K27me3 at a small subset of genes is closely involved in DIPG. The residual PRC2 activity is required for the proliferation of H3K27M-expressing DIPGs, and the inhibition of EZH2 is a potential therapeutic strategy [62▪].


By epigenetically regulating the transcriptome, EZH2 is involved in oncogenic processes, including cell cycle regulation, abnormal differentiation, epithelial–mesenchymal transition [63,64], and other cancer type-specific characteristics [35]. In addition, tumor immunity has emerged as a process that involves the EZH2 regulatory network. EZH2/PRC2 represses tumor production of the T helper 1 chemokines CXCL9 and CXCL10 and influences the effector T-cell trafficking to the tumor microenvironment in ovarian and colon cancers [65▪▪,66]. Inhibitors against EZH2 and DNMT increase CXCL9 and CXCL10 production, improve tumor clearance, and facilitate the efficacy of the PD-L1 checkpoint blockade and adoptive T-cell transfusion in a mouse model. The possible function of EZH2 in immune evasion suggests that appropriate reprogramming of the cancer epigenome is promising in developing a more effective therapy.

PRC2-independent, noncanonical oncogenic functions of EZH2 have been reported. EZH2 plays a role as a coactivator for the androgen receptor in castration-resistant prostate cancer [31]. In glioblastoma stem-like cells, EZH2 methylates STAT3, leading to enhanced STAT3 activity [32]. Targeting the non-PRC2 function of EZH2 may have therapeutic efficacy in treating some specific cancer types.

In addition, EZH2 is aberrant in malignant progenitors. For example, H3K27me3 accumulation and subsequent gene repression have been observed in HTLV-1-infected immortalized cells [25▪▪,67]. The HTLV-1 oncoprotein Tax binds to EZH2 and affects its function and distribution. These critical data imply that epigenetic disorders occur in the early phase of tumorigenesis, for example, induced by viral infection (Fig. 3).

Epigenetic dysregulation in the early phase of tumorigenesis. A proposed model for the cancer development initiated by epigenetic disorders. EZH2-dependent abnormal transcriptome is partially established in nonmalignant, immortalized cells. The following cancer development is accelerated by accumulation of genetic and epigenetic changes.


Great efforts from researchers and industries have developed epigenetic drugs specifically targeting EZH2, which have been verified in vivo and in some clinical trials.

Although the first-generation inhibitor DZNep has been used in several basic studies to investigate the roles of EZH2, its nonspecificity has been indicated. In 2012, potent, highly selective S-adenosyl-methionine-competitive small molecule inhibitors of EZH2 methyltransferase activity were developed. GSK126 [68] and EPZ005687 [69] are selective EZH2 inhibitors that can bind to the EZH2 wild-type and Y641 mutant, leading to diminished H3K27me3 level and upregulation of the silenced transcription. The pharmacological inhibition of EZH2 activity can effectively inhibit the proliferation of the EZH2 mutant DLBCL both in vitro and in xenograft mouse models [14,15▪,68,69]. Another oral EZH2 inhibitor, EPZ6438 (tazemetostat), is currently under evaluation in a phase 1/2 clinical trial in patients with B-cell lymphomas and advanced solid tumors (NCT01897571), which has provided preliminary signs of clinical activity [10]. Consistent with the preclinical studies, the synthetic lethality in cancers that are deficient in SMARCB1 or SMARCA4 has been clinically implicated. This concept is being further evaluated in pediatric (NCT02601937) and adult (NCT02601950) patients with relapsed malignancies, including malignant rhabdoid tumors (SMARCB1-negative) and synovial sarcomas.

Simultaneous inhibition of EZH2 and an another H3K27me3 methyltransferase EZH1 is an advanced strategy for targeting accumulated H3K27me3 because EZH1 compensates for EZH2 [70,71]. The EZH1/2 dual inhibition is expected to treat MLL-rearranged leukemia [72] and aggressive T-cell and B-cell lymphomas [73▪▪,74▪]. DS-3201b is a novel, orally available EZH1/2 dual inhibitor, and it is being clinically evaluated in patients with non-Hodgkin's lymphomas, including ATL (NCT02732275) and acute myelogenous leukemia or ALL (NCT03110354).

For manipulation of the abnormal actions of EZH2/PRC2, other potential strategies are being proposed, including targeted disruption of the EZH2-EED complex [75] and allosteric PRC2 inhibition targeting the H3K27me3 binding pocket of EED [76]. The transcription regulation of upregulated EZH2 is conceptually regarded, possibly by targeting NF-κB and ERK.


EZH2-dependent cancer types are being actively discussed. Importantly, the reduction rate of H3K27me3 level after EZH2 inhibition is not correlated with cell viability. To establish the precision medicine, we should understand the true EZH2-dependency of tumor cells defined based on the genetic and epigenetic landscapes, origin of the tumor cell, and history of the tumor [35]. Seeking vulnerability and its combination for H3K27me3-dependent cancer will pave the ways for more effective, low toxic therapy targeting cancer epigenome that is a reversible characteristic (cf. genetic alteration).


EZH2 is a master regulator of cancer-associated epigenetic disorders. Appropriate manipulation of EZH2/PRC2 may provide great promise for cancer therapy. Given that EZH2 is of prime importance in the gene regulatory body, precise understanding at a wide resolution range (i.e., from molecular level to cluster network) will lead to the next phase of basic and clinical biology.


We would like to thank Professor Toshiki Watanabe, St. Marianna University Graduate School of Medicine, for his advice on the ATL work.

Financial support and sponsorship

This work was supported by the Research programs (No. 17fk0108112h0001, 17im0210101h0203, and 17fk0410208h0002) from the Japan Agency for Medical Research and Development (AMED) and JSPS KAKENHI Grant Numbers 15K06907 and 16H05323.

The authors have received a research grant from Daiichi Sankyo Co., Ltd.

Conflicts of interest

There are no conflicts of interest.


Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest


1. Bradner JE, Hnisz D, Young RA. Transcriptional addiction in cancer. Cell 2017; 168:629–643.
2. Rivera CM, Ren B. Mapping human epigenomes. Cell 2013; 155:39–55.
3. Jones PA, Baylin SB. The epigenomics of cancer. Cell 2007; 128:683–692.
4. Helin K, Dhanak D. Chromatin proteins and modifications as drug targets. Nature 2013; 502:480–488.
5. Sparmann A, van Lohuizen M. Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer 2006; 6:846–856.
6. Margueron R, Reinberg D. The polycomb complex PRC2 and its mark in life. Nature 2011; 469:343–349.
7. Mills AA. Throwing the cancer switch: reciprocal roles of polycomb and trithorax proteins. Nat Rev Cancer 2010; 10:669–682.
8. Hohmann AF, Vakoc CR. A rationale to target the SWI/SNF complex for cancer therapy. Trends Genet 2014; 30:356–363.
9. Kadoch C, Crabtree GR. Mammalian SWI/SNF chromatin remodeling complexes and cancer: mechanistic insights gained from human genomics. Sci Adv 2015; 1:e1500447–e11500447.
10. Kim KH, Roberts CWM. Targeting EZH2 in cancer. Nat Med 2016; 22:128–134.
11. Morin RD, Johnson NA, Severson TM, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet 2010; 42:181–185.
12. McCabe MT, Graves AP, Ganji G, et al. 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 USA 2012; 109:2989–2994.
13. Yap DB, Chu J, Berg T, et al. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood 2011; 117:2451–2459.
14. Béguelin W, Popovic R, Teater M, et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell 2013; 23:677–692.
15▪. Souroullas GP, Jeck WR, Parker JS, et al. An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation. Nat Med 2016; 22:632–640.
16. Ernst T, Chase AJ, Score J, et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet 2010; 42:722–726.
17. Nikoloski G, Langemeijer SM, Kuiper RP, et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet 2010; 42:665–667.
18. Ntziachristos P, Tsirigos A, Vlierberghe PV, et al. Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nat Med 2012; 18:298–303.
19. Lund K, Adams PD, Copland M. EZH2 in normal and malignant hematopoiesis. Leukemia 2013; 28:44–49.
20. Varambally S, Dhanasekaran SM, Zhou M, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 2002; 419:624–629.
21. Bracken AP, Pasini D, Capra M, et al. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J 2003; 22:5323–5335.
22. Fujii S, Tokita K, Wada N, et al. MEK–ERK pathway regulates EZH2 overexpression in association with aggressive breast cancer subtypes. Oncogene 2011; 30:4118–4128.
23. Riquelme E, Behrens C, Lin HY, et al. Modulation of EZH2 expression by MEK-ERK or PI3K-AKT signaling in lung cancer is dictated by different KRAS oncogene mutations. Cancer Res 2016; 76:675–685.
24. Chang CJ, Yang JY, Xia W, et al. EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-β-catenin signaling. Cancer Cell 2011; 19:86–100.
25▪▪. Fujikawa D, Nakagawa S, Hori M, et al. Polycomb-dependent epigenetic landscape in adult T-cell leukemia. Blood 2016; 127:1790–1802.
26. Yamagishi M, Nakano K, Miyake A, et al. Polycomb-mediated loss of miR-31 activates NIK-dependent NF-κB pathway in adult T cell leukemia and other cancers. Cancer Cell 2012; 21:121–135.
27. Varambally S, Cao Q, Mani RS, et al. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science 2008; 322:1695–1699.
28. Sander S, Bullinger L, Klapproth K, et al. MYC stimulates EZH2 expression by repression of its negative regulator miR-26a. Blood 2008; 112:4202–4212.
29. Zhang X, Zhao X, Fiskus W, et al. Coordinated silencing of MYC-mediated miR-29 by HDAC3 and EZH2 as a therapeutic target of histone modification in aggressive B-cell lymphomas. Cancer Cell 2012; 22:506–523.
30. Cha TL, Zhou BP, Xia W, et al. Akt-mediated phosphorylation of EZH2 suppresses methylation of lysine 27 in histone H3. Science 2005; 310:306–310.
31. Xu K, Wu ZJ, Groner AC, et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is polycomb-independent. Science 2012; 338:1465–1469.
32. Kim E, Kim M, Woo DH, et al. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell 2013; 23:839–852.
33. Chen S, Bohrer LR, Rai AN, et al. Cyclin-dependent kinases regulate epigenetic gene silencing through phosphorylation of EZH2. Nat Cell Biol 2010; 12:1108–1114.
34. Wei Y, Chen YH, Li LY, et al. CDK1-dependent phosphorylation of EZH2 suppresses methylation of H3K27 and promotes osteogenic differentiation of human mesenchymal stem cells. Nat Cell Biol 2010; 13:87–94.
35. Comet I, Riising EM, Leblanc B, Helin K. Maintaining cell identity: PRC2-mediated regulation of transcription and cancer. Nat Rev Cancer 2016; 16:803–810.
36. Yamagishi M, Watanabe T. Molecular hallmarks of adult T cell leukemia. Front Microbiol 2012; 3:334.
37. Asangani IA, Harms PW, Dodson L, et al. Genetic and epigenetic loss of microRNA-31 leads to feed-forward expression of EZH2 in melanoma. Oncotarget 2012; 3:1011–1025.
38. Min J, Zaslavsky A, Fedele G, et al. An oncogene–tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-κB. Nat Med 2010; 16:286–294.
39. Lee ST, Li Z, Wu Z, et al. Context-specific regulation of NF-κB target gene expression by EZH2 in breast cancers. Mol Cell 2011; 43:798–810.
40. Huntzinger E, Izaurralde E. Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet 2011; 12:99–110.
41. Ling H, Fabbri M, Calin GA. MicroRNAs and other noncoding RNAs as targets for anticancer drug development. Nat Rev Drug Discov 2013; 12:847–865.
42. Lin PC, Chiu YL, Banerjee S, et al. Epigenetic repression of miR-31 disrupts androgen receptor homeostasis and contributes to prostate cancer progression. Cancer Res 2013; 73:1232–1244.
43. Iliopoulos D, Lindahl-Allen M, Polytarchou C, et al. Loss of miR-200 inhibition of Suz12 leads to polycomb-mediated repression required for the formation and maintenance of cancer stem cells. Mol Cell 2010; 39:761–772.
44. Cao Q, Mani RS, Ateeq B, et al. Coordinated regulation of polycomb group complexes through microRNAs in cancer. Cancer Cell 2011; 20:187–199.
45. Kadoch C, Hargreaves DC, Hodges C, et al. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat Genet 2013; 45:592–601.
46. Lawrence MS, Stojanov P, Mermel CH, et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 2014; 505:495–501.
47. Pfister SX, Ashworth A. Marked for death: targeting epigenetic changes in cancer. Nat Rev Drug Discov 2017; 16:241–263.
48. Wilson BG, Wang X, Shen X, et al. Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. Cancer Cell 2010; 18:316–328.
49▪. Kadoch C, Williams RT, Calarco JP, et al. Dynamics of BAF–polycomb complex opposition on heterochromatin in normal and oncogenic states. Nat Genet 2016; 49:213–222.
50▪▪. Bitler BG, Aird KM, Garipov A, et al. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat Med 2015; 21:231–238.
51. Wiegand KC, Shah SP, Al-Agha OM, et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med 2010; 363:1532–1543.
52. Jones S, Wang TL, Shih le M, et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 2010; 330:228–231.
53▪. Kim KH, Kim W, Howard TP, et al. SWI/SNF-mutant cancers depend on catalytic and noncatalytic activity of EZH2. Nat Med 2015; 21:1491–1496.
54▪. Fillmore CM, Xu C, Desai PT, et al. EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumours to TopoII inhibitors. Nature 2015; 520:239–242.
55. Scheuermann JC, de Ayala Alonso AG, Oktaba K, et al. Histone H2A deubiquitinase activity of the polycomb repressive complex PR-DUB. Nature 2010; 465:243–247.
56▪. LaFave LM, Béguelin W, Koche R, et al. Loss of BAP1 function leads to EZH2-dependent transformation. Nat Med 2015; 21:1344–1349.
57. van Haaften G, Dalgliesh GL, Davies H, et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat Genet 2009; 41:521–523.
58▪. Ler LD, Ghosh S, Chai X, et al. Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2. Sci Transl Med 2017; 9:eaai8312.
59. Schwartzentruber J, Korshunov A, Liu XY, et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 2012; 482:226–231.
60. Lewis PW, Müller MM, Koletsky MS, et al. Inhibition of PRC2 activity by a gain-of-function H3 H3 mutation found in pediatric glioblastoma. Science 2013; 340:857–861.
61. Bender S, Tang Y, Lindroth AM, et al. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27 M mutant pediatric high-grade gliomas. Cancer Cell 2013; 24:660–672.
62▪. Mohammad F, Weissmann S, Leblanc B, et al. EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas. Nat Med 2017; 23:483–492.
63. Cao Q, Yu J, Dhanasekaran SM, et al. Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene 2008; 27:7274–7284.
64. Tiwari N, Tiwari VK, Waldmeier L, et al. Sox4 is a master regulator of epithelial-mesenchymal transition by controlling Ezh2 expression and epigenetic reprogramming. Cancer Cell 2013; 23:768–783.
65▪▪. Peng D, Kryczek I, Nagarsheth N, et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 2015; 527:249–253.
66. Nagarsheth N, Peng D, Kryczek I, et al. PRC2 epigenetically silences Th1-type chemokines to suppress effector T-cell trafficking in colon cancer. Cancer Res 2016; 76:275–282.
67. Kobayashi S, Nakano K, Watanabe E, et al. CADM1 expression and stepwise downregulation of CD7 are closely associated with clonal expansion of HTLV-I-infected cells in adult T-cell leukemia/lymphoma. Clin Cancer Res 2014; 20:2851–2861.
68. McCabe MT, Ott HM, Ganji G, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 2012; 492:108–112.
69. Knutson SK, Wigle TJ, Warholic NM, et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol 2012; 8:890–896.
70. Shen X, Liu Y, Hsu YJ, et al. EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. Mol Cell 2008; 32:491–502.
71. Margueron R, Li G, Sarma K, et al. Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms. Mol Cell 2008; 32:503–518.
72. Xu B, On DM, Ma A, et al. Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia. Blood 2015; 125:346–357.
73▪▪. Yamagishi M, Fujikawa D, Honma D, et al. Polycomb-dependent epigenetic landscape in adult T cell leukemia (ATL); providing proof of concept for targeting EZH1/2 to selectively eliminate the HTLV-1 infected population. Blood 2015; 126:572(meeting abstract).
74▪. Yamagishi M, Hori M, Fujikawa D, et al. Development and molecular analysis of synthetic lethality by targeting EZH1 and EZH2 in non-Hodgkin lymphomas. Blood 2016; 128:462(meeting abstract).
75. Kim W, Bird GH, Neff T, et al. Targeted disruption of the EZH2-EED complex inhibits EZH2-dependent cancer. Nat Chem Biol 2013; 9:643–650.
76. Qi W, Zhao K, Gu J, et al. An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED. Nat Chem Biol 2017; 13:381–388.

chromatin regulation; epigenetics; EZH2; transcriptome

Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc.