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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2019

Open Access 01-12-2019 | Lymphoma | Review

EZH2 abnormalities in lymphoid malignancies: underlying mechanisms and therapeutic implications

Authors: Boheng Li, Wee-Joo Chng

Published in: Journal of Hematology & Oncology | Issue 1/2019

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Abstract

EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2), which along with other PRC2 components mediates gene expression suppression via the methylation of Histone H3 at lysine 27. Recent studies have revealed a dichotomous role of EZH2 in physiology and in the pathogenesis of cancer. While it plays an essential role in the development of the lymphoid system, its deregulation, whether due to genetic or non-genetic causes, promotes B cell- and T cell-related lymphoma or leukemia. These findings triggered a boom in the development of therapeutic EZH2 inhibitors in recent years. Here, we discuss physiologic and pathogenic function of EZH2 in lymphoid context, various internal causes of EZH2 aberrance and how EZH2 modulates lymphomagenesis through epigenetic silencing, post-translational modifications (PTMs), orchestrating with surrounding tumor micro-environment and associating with RNA or viral partners. We also summarize different strategies to directly inhibit PRC2-EZH2 or to intervene EZH2 upstream signaling.
Literature
1.
2.
Simon JA, Lange CA. Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutation Res. 2008;647:21–9.PubMedCrossRef
3.
Boyer LA, Latek RR, Peterson CL. The SANT domain: a unique histone-tail-binding module? Nat Rev Mol Cell Biol. 2004;5:158–63.PubMedCrossRef
4.
Li F, Zeng Z, Xing S, Gullicksrud JA, Shan Q, Choi J, Badovinac VP, Crotty S, Peng W, Xue HH. Ezh2 programs TFH differentiation by integrating phosphorylation-dependent activation of Bcl6 and polycomb-dependent repression of p19Arf. Nat Commun. 2018;9:5452.PubMedPubMedCentralCrossRef
5.
Gray SM, Amezquita RA, Guan T, Kleinstein SH, Kaech SM. Polycomb repressive complex 2-mediated chromatin repression guides effector CD8(+) T cell terminal differentiation and loss of multipotency. Immunity. 2017;46:596–608.PubMedPubMedCentralCrossRef
6.
He S, Liu Y, Meng L, Sun H, Wang Y, Ji Y, Purushe J, Chen P, Li C, Madzo J, Issa JP, Soboloff J, Reshef R, Moore B, Gattinoni L, Zhang Y. Ezh2 phosphorylation state determines its capacity to maintain CD8(+) T memory precursors for antitumor immunity. Nat Commun. 2017;8:2125.PubMedPubMedCentralCrossRef
7.
Tumes DJ, Onodera A, Suzuki A, Shinoda K, Endo Y, Iwamura C, Hosokawa H, Koseki H, Tokoyoda K, Suzuki Y, Motohashi S, Nakayama T. The polycomb protein Ezh2 regulates differentiation and plasticity of CD4(+) T helper type 1 and type 2 cells. Immunity. 2013;39:819–32.PubMedCrossRef
8.
Xiong Y, Khanna S, Grzenda AL, Sarmento OF, Svingen PA, Lomberk GA, Urrutia RA, Faubion WA Jr. Polycomb antagonizes p300/CREB-binding protein-associated factor to silence FOXP3 in a Kruppel-like factor-dependent manner. J Biol Chem. 2012;287:34372–85.PubMedPubMedCentralCrossRef
9.
Arvey A, van der Veeken J, Samstein RM, Feng Y, Stamatoyannopoulos JA, Rudensky AY. Inflammation-induced repression of chromatin bound by the transcription factor Foxp3 in regulatory T cells. Nat Immunol. 2014;15:580–7.PubMedPubMedCentralCrossRef
10.
Koyanagi M, Baguet A, Martens J, Margueron R, Jenuwein T, Bix M. EZH2 and histone 3 trimethyl lysine 27 associated with Il4 and Il13 gene silencing in Th1 cells. J Biol Chem. 2005;280:31470–7.PubMedCrossRef
11.
Wang A, Pan D, Lee YH, Martinez GJ, Feng XH, Dong C. Cutting edge: Smad2 and Smad4 regulate TGF-beta-mediated Il9 gene expression via EZH2 displacement. J Immunol. 1950;191(2013):4908–12.
12.
Zhang Y, Kinkel S, Maksimovic J, Bandala-Sanchez E, Tanzer MC, Naselli G, Zhang JG, Zhan Y, Lew AM, Silke J, Oshlack A, Blewitt ME, Harrison LC. The polycomb repressive complex 2 governs life and death of peripheral T cells. Blood. 2014;124:737–49.PubMedCrossRef
13.
Chen G, Subedi K, Chakraborty S, Sharov A, Lu J, Kim J, Mi X, Wersto R, Sung MH, Weng NP. Ezh2 regulates activation-induced CD8(+) T cell cycle progression via repressing Cdkn2a and Cdkn1c expression. Frontiers Immunol. 2018;9:549.CrossRef
14.
Dobenecker MW, Kim JK, Marcello J, Fang TC, Prinjha R, Bosselut R, Tarakhovsky A. Coupling of T cell receptor specificity to natural killer T cell development by bivalent histone H3 methylation. J Exp Med. 2015;212:297–306.PubMedPubMedCentralCrossRef
15.
Yang XP, Jiang K, Hirahara K, Vahedi G, Afzali B, Sciume G, Bonelli M, Sun HW, Jankovic D, Kanno Y, Sartorelli V, O’Shea JJ, Laurence A. EZH2 is crucial for both differentiation of regulatory T cells and T effector cell expansion. Sci Rep. 2015;5:10643.PubMedPubMedCentralCrossRef
16.
DuPage M, Chopra G, Quiros J, Rosenthal WL, Morar MM, Holohan D, Zhang R, Turka L, Marson A, Bluestone JA. The chromatin-modifying enzyme Ezh2 is critical for the maintenance of regulatory T cell identity after activation. Immunity. 2015;42:227–38.PubMedPubMedCentralCrossRef
17.
Sarmento OF, Svingen PA, Xiong Y, Sun Z, Bamidele AO, Mathison AJ, Smyrk TC, Nair AA, Gonzalez MM, Sagstetter MR, Baheti S, McGovern DP, Friton JJ, Papadakis KA, Gautam G, Xavier RJ, Urrutia RA, Faubion WA. The role of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) in the Pathobiological mechanisms underlying inflammatory bowel disease (IBD). J Biol Chem. 2017;292:706–22.PubMedCrossRef
18.
Hou S, Clement RL, Diallo A, Blazar BR, Rudensky AY, Sharpe AH, Sage PT. FoxP3 and Ezh2 regulate Tfr cell suppressive function and transcriptional program. J Exp Med. 2019;216:605–20.PubMedPubMedCentralCrossRef
19.
Vasanthakumar A, Xu D, Lun AT, Kueh AJ, van Gisbergen KP, Iannarella N, Li X, Yu L, Wang D, Williams BR, Lee SC, Majewski IJ, Godfrey DI, Smyth GK, Alexander WS, Herold MJ, Kallies A, Nutt SL, Allan RS. A non-canonical function of Ezh2 preserves immune homeostasis. EMBO Rep. 2017;18:619–31.PubMedPubMedCentralCrossRef
20.
Wang Y, Sun H, Wang J, Wang H, Meng L, Xu C, Jin M, Wang B, Zhang Y, Zhang Y, Zhu T. DNA-PK-mediated phosphorylation of EZH2 regulates the DNA damage-induced apoptosis to maintain T-cell genomic integrity. Cell Death Dis. 2016;7:e2316.PubMedPubMedCentralCrossRef
21.
Dobenecker MW, Park JS, Marcello J, McCabe MT, Gregory R, Knight SD, Rioja I, Bassil AK, Prinjha RK, Tarakhovsky A. Signaling function of PRC2 is essential for TCR-driven T cell responses. J Biol Chem. 2018;215:1101–13.
22.
Su IH, Basavaraj A, Krutchinsky AN, Hobert O, Ullrich A, Chait BT, Tarakhovsky A. Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement. Nat Immunol. 2003;4:124–31.PubMedCrossRef
23.
Stebegg M, Kumar SD, Silva-Cayetano A, Fonseca VR, Linterman MA, Graca L. Regulation of the germinal center response. Frontiers Immunol. 2018;9:2469.CrossRef
24.
Baxter J, Sauer S, Peters A, John R, Williams R, Caparros ML, Arney K, Otte A, Jenuwein T, Merkenschlager M, Fisher AG. Histone hypomethylation is an indicator of epigenetic plasticity in quiescent lymphocytes. EMBO J. 2004;23:4462–72.PubMedPubMedCentralCrossRef
25.
Herviou L, Jourdan M, Martinez AM, Cavalli G, Moreaux J. EZH2 is overexpressed in transitional preplasmablasts and is involved in human plasma cell differentiation. Leukemia. 2019;12:1.
26.
Velichutina I, Shaknovich R, Geng H, Johnson NA, Gascoyne RD, Melnick AM, Elemento O. EZH2-mediated epigenetic silencing in germinal center B cells contributes to proliferation and lymphomagenesis. Blood. 2010;116:5247–55.PubMedPubMedCentralCrossRef
27.
Beguelin W, Rivas MA, Calvo Fernandez MT, Teater M, Purwada A, Redmond D, Shen H, Challman MF, Elemento O, Singh A, Melnick AM. EZH2 enables germinal centre formation through epigenetic silencing of CDKN1A and an Rb-E2F1 feedback loop. Nat Commun. 2017;8:877.PubMedPubMedCentralCrossRef
28.
Beguelin W, Popovic R, Teater M, Jiang Y, Bunting KL, Rosen M, Shen H, Yang SN, Wang L, Ezponda T, Martinez-Garcia E, Zhang H, Zheng Y, Verma SK, McCabe MT, Ott HM, Van Aller GS, Kruger RG, Liu Y, McHugh CF, Scott DW, Chung YR, Kelleher N, Shaknovich R, Creasy CL, Gascoyne RD, Wong KK, Cerchietti L, Levine RL, Abdel-Wahab O, Licht JD, Elemento O, Melnick AM. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell. 2013;23:677–92.PubMedPubMedCentralCrossRef
29.
Caganova M, Carrisi C, Varano G, Mainoldi F, Zanardi F, Germain PL, George L, Alberghini F, Ferrarini L, Talukder AK, Ponzoni M, Testa G, Nojima T, Doglioni C, Kitamura D, Toellner KM, Su IH, Casola S. Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis. J Clin Invest. 2013;123:5009–22.PubMedPubMedCentralCrossRef
30.
Guo M, Price MJ, Patterson DG, Barwick BG, Haines RR, Kania AK, Bradley JE, Randall TD, Boss JM, Scharer CD. EZH2 represses the B cell transcriptional program and regulates antibody-secreting cell metabolism and antibody production. J Immunol. 1950;200(2018):1039–52.
31.
Bouska A, Zhang W, Gong Q, Iqbal J, Scuto A, Vose J, Ludvigsen M, Fu K, Weisenburger DD, Greiner TC, Gascoyne RD, Rosenwald A, Ott G, Campo E, Rimsza LM, Delabie J, Jaffe ES, Braziel RM, Connors JM, Wu CI, Staudt LM, D'Amore F, McKeithan TW, Chan WC. Combined copy number and mutation analysis identifies oncogenic pathways associated with transformation of follicular lymphoma. Leukemia. 2017;31:83–91.PubMedCrossRef
32.
Majer CR, Jin L, Scott MP, Knutson SK, Kuntz KW, Keilhack H, Smith JJ, Moyer MP, Richon VM, Copeland RA, Wigle TJ. A687V EZH2 is a gain-of-function mutation found in lymphoma patients. FEBS Lett. 2012;586:3448–51.PubMedCrossRef
33.
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. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010;42:181–5.PubMedPubMedCentralCrossRef
34.
Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD, Johnson NA, Severson TM, Chiu R, Field M, Jackman S, Krzywinski M, Scott DW, Trinh DL, Tamura-Wells J, Li S, Firme MR, Rogic S, Griffith M, Chan S, Yakovenko O, Meyer IM, Zhao EY, Smailus D, Moksa M, Chittaranjan S, Rimsza L, Brooks-Wilson A, Spinelli JJ, Ben-Neriah S, Meissner B, Woolcock B, Boyle M, McDonald H, Tam A, Zhao Y, Delaney A, Zeng T, Tse K, Butterfield Y, Birol I, Holt R, Schein J, Horsman DE, Moore R, Jones SJ, Connors JM, Hirst M, Gascoyne RD, Marra MA. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011;476:298–303.PubMedPubMedCentralCrossRef
35.
McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS, Liu Y, Graves AP, Della Pietra A, 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. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012;492:108–12.CrossRefPubMed
36.
Wigle TJ, Knutson SK, Jin L, Kuntz KW, Pollock RM, Richon VM, Copeland RA, Scott MP. The Y641C mutation of EZH2 alters substrate specificity for histone H3 lysine 27 methylation states. FEBS Lett. 2011;585:3011–4.PubMedCrossRef
37.
38.
Yap DB, Chu J, Berg T, Schapira M, Cheng SW, Moradian A, Morin RD, Mungall AJ, Meissner B, Boyle M, Marquez VE, Marra MA, Gascoyne RD, Humphries RK, Arrowsmith CH, Morin GB, Aparicio SA. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood. 2011;117:2451–9.PubMedPubMedCentralCrossRef
39.
Souroullas GP, Jeck WR, Parker JS, Simon JM, Liu JY, Paulk J, Xiong J, Clark KS, Fedoriw Y, Qi J, Burd CE, Bradner JE, Sharpless NE. An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation. Nat Med. 2016;22:632–40.PubMedPubMedCentralCrossRef
40.
Sneeringer CJ, Scott MP, Kuntz KW, Knutson SK, Pollock RM, Richon VM, Copeland RA. 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. 2010;107:20980–5.PubMedPubMedCentralCrossRef
41.
Sahasrabuddhe AA, Chen X, Chung F, Velusamy T, Lim MS, Elenitoba-Johnson KS. Oncogenic Y641 mutations in EZH2 prevent Jak2/beta-TrCP-mediated degradation. Oncogene. 2015;34:445–54.PubMedCrossRef
42.
McCabe MT, Graves AP, Ganji G, Diaz E, Halsey WS, Jiang Y, Smitheman KN, Ott HM, Pappalardi MB, Allen KE, Chen SB, Della Pietra A 3rd, Dul E, Hughes AM, Gilbert SA, Thrall SH, Tummino PJ, Kruger RG, Brandt M, Schwartz B, Creasy CL. 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. 2012;109:2989–94.PubMedPubMedCentralCrossRef
43.
Burgos S, Montalban-Bravo G, Fuente L, Jabbour EJ, Kanagal-Shamanna R, Soltysiak KA, Garcia-Manero G, Mela-Osorio MJ. Novel EZH2 mutation in a patient with secondary B-cell acute lymphocytic leukemia after deletion 5q myelodysplastic syndrome treated with lenalidomide: a case report. Medicine. 2019;98:e14011.PubMedPubMedCentralCrossRef
44.
Schafer V, Ernst J, Rinke J, Winkelmann N, Beck JF, Hochhaus A, Gruhn B, Ernst T. EZH2 mutations and promoter hypermethylation in childhood acute lymphoblastic leukemia. J Cancer Res Clin Oncol. 2016;142:1641–50.PubMedCrossRef
45.
Neumann M, Vosberg S, Schlee C, Heesch S, Schwartz S, Gokbuget N, Hoelzer D, Graf A, Krebs S, Bartram I, Blum H, Bruggemann M, Hecht J, Bohlander SK, Greif PA, Baldus CD. Mutational spectrum of adult T-ALL. Oncotarget. 2015;6:2754–66.PubMedCrossRef
46.
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. Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nat Med. 2012;18:298–301.PubMedPubMedCentralCrossRef
47.
Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne-Turner D, Easton J, Chen X, Wang J, Rusch M, Lu C, Chen SC, Wei L, Collins-Underwood JR, Ma J, Roberts KG, Pounds SB, Ulyanov A, Becksfort J, Gupta P, Huether R, Kriwacki RW, Parker M, McGoldrick DJ, Zhao D, Alford D, Espy S, Bobba KC, Song G, Pei D, Cheng C, Roberts S, Barbato MI, Campana D, Coustan-Smith E, Shurtleff SA, Raimondi SC, Kleppe M, Cools J, Shimano KA, Hermiston ML, Doulatov S, Eppert K, Laurenti E, Notta F, Dick JE, Basso G, Hunger SP, Loh ML, Devidas M, Wood B, Winter S, Dunsmore KP, Fulton RS, Fulton LL, Hong X, Harris CC, Dooling DJ, Ochoa K, Johnson KJ, Obenauer JC, Evans WE, Pui CH, Naeve CW, Ley TJ, Mardis ER, Wilson RK, Downing JR, Mullighan CG. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature. 2012;481:157–63.PubMedPubMedCentralCrossRef
48.
Richter J, Schlesner M, Hoffmann S, Kreuz M, Leich E, Burkhardt B, Rosolowski M, Ammerpohl O, Wagener R, Bernhart SH, Lenze D, Szczepanowski M, Paulsen M, Lipinski S, Russell RB, Adam-Klages S, Apic G, Claviez A, Hasenclever D, Hovestadt V, Hornig N, Korbel JO, Kube D, Langenberger D, Lawerenz C, Lisfeld J, Meyer K, Picelli S, Pischimarov J, Radlwimmer B, Rausch T, Rohde M, Schilhabel M, Scholtysik R, Spang R, Trautmann H, Zenz T, Borkhardt A, Drexler HG, Moller P, MacLeod RA, Pott C, Schreiber S, Trumper L, Loeffler M, Stadler PF, Lichter P, Eils R, Kuppers R, Hummel M, Klapper W, Rosenstiel P, Rosenwald A, Brors B, Siebert R. Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing. Nat Genet. 2012;44:1316–20.PubMedCrossRef
49.
Lue JK, Amengual JE. Emerging EZH2 inhibitors and their application in lymphoma. Curr Hematol Malig Rep. 2018;13:369–82.PubMedCrossRef
50.
Schmitz R, Wright GW, Huang DW, Johnson CA, Phelan JD, Wang JQ, Roulland S, Kasbekar M, Young RM, Shaffer AL, Hodson DJ, Xiao W, Yu X, Yang Y, Zhao H, Xu W, Liu X, Zhou B, Du W, Chan WC, Jaffe ES, Gascoyne RD, Connors JM, Campo E, Lopez-Guillermo A, Rosenwald A, Ott G, Delabie J, Rimsza LM, Wei KTK, Zelenetz AD, Leonard JP, Bartlett NL, Tran B, Shetty J, Zhao Y, Soppet DR, Pittaluga S, Wilson WH, Staudt LM. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med. 2018;378:1396–407.PubMedPubMedCentralCrossRef
51.
Zhao X, Lwin T, Zhang X, Huang A, Wang J, Marquez VE, Chen-Kiang S, Dalton WS, Sotomayor E, Tao J. Disruption of the MYC-miRNA-EZH2 loop to suppress aggressive B-cell lymphoma survival and clonogenicity. Leukemia. 2013;27:2341–50.PubMedPubMedCentralCrossRef
52.
Yan J, Ng SB, Tay JL, Lin B, Koh TL, Tan J, Selvarajan V, Liu SC, Bi C, Wang S, Choo SN, Shimizu N, Huang G, Yu Q, Chng WJ. EZH2 overexpression in natural killer/T-cell lymphoma confers growth advantage independently of histone methyltransferase activity. Blood. 2013;121:4512–20.PubMedCrossRef
53.
Sander S, Bullinger L, Klapproth K, Fiedler K, Kestler HA, Barth TF, Moller P, Stilgenbauer S, Pollack JR, Wirth T. MYC stimulates EZH2 expression by repression of its negative regulator miR-26a. Blood. 2008;112:4202–12.PubMedCrossRef
54.
Zhang X, Zhao X, Fiskus W, Lin J, Lwin T, Rao R, Zhang Y, Chan JC, Fu K, Marquez VE, Chen-Kiang S, Moscinski LC, Seto E, Dalton WS, Wright KL, Sotomayor E, Bhalla K, Tao J. 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;22:506–23.PubMedPubMedCentralCrossRef
55.
Rastgoo N, Pourabdollah M, Abdi J, Reece D, Chang H. Dysregulation of EZH2/miR-138 axis contributes to drug resistance in multiple myeloma by downregulating RBPMS. Leukemia. 2018;32:2471–82.PubMedCrossRef
56.
Neo WH, Lim JF, Grumont R, Gerondakis S, Su IH. C-Rel regulates Ezh2 expression in activated lymphocytes and malignant lymphoid cells. J Biol Chem. 2014;289:31693–707.PubMedPubMedCentralCrossRef
57.
Croonquist PA, Van Ness B. The polycomb group protein enhancer of zeste homolog 2 (EZH 2) is an oncogene that influences myeloma cell growth and the mutant ras phenotype. Oncogene. 2005;24:6269–80.PubMedCrossRef
58.
Li B, Yan J, Phyu T, Fan S, Chung TH, Mustafa NB, Lin B, Wang L, Eichhorn PJA, Goh BC, Ng SB, Kappei D, Chng WJ. MELK mediates the stability of EZH2 through site-specific phosphorylation in extranodal natural killer/T-cell lymphoma. Blood. 2019.
59.
Iannetti A, Ledoux AC, Tudhope SJ, Sellier H, Zhao B, Mowla S, Moore A, Hummerich H, Gewurz BE, Cockell SJ, Jat PS, Willmore E, Perkins ND. Regulation of p53 and Rb links the alternative NF-kappaB pathway to EZH2 expression and cell senescence. PLoS Genet. 2014;10:e1004642.PubMedPubMedCentralCrossRef
60.
Wang C, Oshima M, Sato D, Matsui H, Kubota S, Aoyama K, Nakajima-Takagi Y, Koide S, Matsubayashi J, Mochizuki-Kashio M, Nakano-Yokomizo T, Bai J, Nagao T, Kanai A, Iwama A, Sashida G. Ezh2 loss propagates hypermethylation at T cell differentiation-regulating genes to promote leukemic transformation. J Clin Invest. 2018;128:3872–86.PubMedPubMedCentralCrossRef
61.
Sehgal L, Mathur R, Braun FK, Wise JF, Berkova Z, Neelapu S, Kwak LW, Samaniego F. FAS-antisense 1 lncRNA and production of soluble versus membrane FAS in B-cell lymphoma. Leukemia. 2014;28:2376–87.PubMedPubMedCentralCrossRef
62.
Chen J, Li J, Han Q, Sun Z, Wang J, Wang S, Zhao RC. Enhancer of zeste homolog 2 is overexpressed and contributes to epigenetic inactivation of p21 and phosphatase and tensin homolog in B-cell acute lymphoblastic leukemia. Exp Biol Med. 2012;237:1110–6.CrossRef
63.
Agarwal P, Alzrigat M, Parraga AA, Enroth S, Singh U, Ungerstedt J, Osterborg A, Brown PJ, Ma A, Jin J, Nilsson K, Oberg F, Kalushkova A, Jernberg-Wiklund H. Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target. Oncotarget. 2016;7:6809–23.PubMedPubMedCentral
64.
Giambra V, Gusscott S, Gracias D, Song R, Lam SH, Panelli P, Tyshchenko K, Jenkins CE, Hoofd C, Lorzadeh A, Carles A, Hirst M, Eaves CJ, Weng AP. Epigenetic restoration of fetal-like IGF1 signaling inhibits leukemia stem cell activity. Cell Stem Cell. 2018;23:714–726.e717.PubMedCrossRef
65.
Aries IM, Bodaar K, Karim SA, Chonghaile TN, Hinze L, Burns MA, Pfirrmann M, Degar J, Landrigan JT, Balbach S, Peirs S, Menten B, Isenhart R, Stevenson KE, Neuberg DS, Devidas M, Loh ML, Hunger SP, Teachey DT, Rabin KR, Winter SS, Dunsmore KP, Wood BL, Silverman LB, Sallan SE, Van Vlierberghe P, Orkin SH, Knoechel B, Letai AG, Gutierrez A. PRC2 loss induces chemoresistance by repressing apoptosis in T cell acute lymphoblastic leukemia. J Exp Med. 2018;215:3094–114.PubMedPubMedCentralCrossRef
66.
Danis E, Yamauchi T, Echanique K, Zhang X, Haladyna JN, Riedel SS, Zhu N, Xie H, Orkin SH, Armstrong SA, Bernt KM, Neff T. Ezh2 controls an early hematopoietic program and growth and survival signaling in early T cell precursor acute lymphoblastic leukemia. Cell Rep. 2016;14:1953–65.PubMedPubMedCentralCrossRef
67.
Schnell SA, Ambesi-Impiombato A, Sanchez-Martin M, Belver L, Xu L, Qin Y, Kageyama R, Ferrando AA. Therapeutic targeting of HES1 transcriptional programs in T-ALL. Blood. 2015;125:2806–14.PubMedPubMedCentralCrossRef
68.
Ishak CA, Marshall AE, Passos DT, White CR, Kim SJ, Cecchini MJ, Ferwati S, MacDonald WA, Howlett CJ, Welch ID, Rubin SM, Mann MRW, Dick FA. An RB-EZH2 complex mediates silencing of repetitive DNA sequences. Mol Cell. 2016;64:1074–87.PubMedPubMedCentralCrossRef
69.
Yan J, Li B, Lin B, Lee PT, Chung TH, Tan J, Bi C, Lee XT, Selvarajan V, Ng SB, Yang H, Yu Q, Chng WJ. EZH2 phosphorylation by JAK3 mediates a switch to noncanonical function in natural killer/T-cell lymphoma. Blood. 2016;128:948–58.PubMedCrossRef
70.
Lee ST, Li Z, Wu Z, Aau M, Guan P, Karuturi RK, Liou YC, Yu Q. Context-specific regulation of NF-kappaB target gene expression by EZH2 in breast cancers. Mol Cell. 2011;43:798–810.PubMedCrossRef
71.
Xu K, Wu ZJ, Groner AC, He HH, Cai C, Lis RT, Wu X, Stack EC, Loda M, Liu T, Xu H, Cato L, Thornton JE, Gregory RI, Morrissey C, Vessella RL, Montironi R, Magi-Galluzzi C, Kantoff PW, Balk SP, Liu XS, Brown M. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science. 2012;338:1465–9.PubMedPubMedCentralCrossRef
72.
Kim J, Lee Y, Lu X, Song B, Fong KW, Cao Q, Licht JD, Zhao JC, Yu J. Polycomb- and methylation-independent roles of EZH2 as a transcription activator. Cell Rep. 2018;25:2808–2820.e2804.PubMedPubMedCentralCrossRef
73.
Yang G, Lu X, Yuan L. LncRNA: a link between RNA and cancer. Biochim Biophys Acta. 2014;1839:1097–109.PubMedCrossRef
74.
Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, Shi Y, Segal E, Chang HY. Long noncoding RNA as modular scaffold of histone modification complexes. Science. 2010;329:689–93.PubMedPubMedCentralCrossRef
75.
Wang L, Zeng X, Chen S, Ding L, Zhong J, Zhao JC, Wang L, Sarver A, Koller A, Zhi J, Ma Y, Yu J, Chen J, Huang H. BRCA1 is a negative modulator of the PRC2 complex. EMBO J. 2013;32:1584–97.PubMedPubMedCentralCrossRef
76.
Kim K, Jutooru I, Chadalapaka G, Johnson G, Frank J, Burghardt R, Kim S, Safe S. HOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer. Oncogene. 2013;32:1616–25.PubMedCrossRef
77.
Liu YW, Sun M, Xia R, Zhang EB, Liu XH, Zhang ZH, Xu TP, De W, Liu BR, Wang ZX. LincHOTAIR epigenetically silences miR34a by binding to PRC2 to promote the epithelial-to-mesenchymal transition in human gastric cancer. Cell Death Dis. 2015;6:e1802.PubMedPubMedCentralCrossRef
78.
Yang SZ, Xu F, Zhou T, Zhao X, McDonald JM, Chen Y. The long non-coding RNA HOTAIR enhances pancreatic cancer resistance to TNF-related apoptosis-inducing ligand. J Biol Chem. 2017;292:10390–7.PubMedPubMedCentralCrossRef
79.
Li CH, Xiao Z, Tong JH, To KF, Fang X, Cheng AS, Chen Y. EZH2 coupled with HOTAIR to silence MicroRNA-34a by the induction of heterochromatin formation in human pancreatic ductal adenocarcinoma. Int J Cancer. 2017;140:120–9.PubMedCrossRef
80.
Chen WM, Chen WD, Jiang XM, Jia XF, Wang HM, Zhang QJ, Shu YQ, Zhao HB. HOX transcript antisense intergenic RNA represses E-cadherin expression by binding to EZH2 in gastric cancer. World J Gastroenterol. 2017;23:6100–10.PubMedPubMedCentralCrossRef
81.
Sun S, Wu Y, Guo W, Yu F, Kong L, Ren Y, Wang Y, Yao X, Jing C, Zhang C, Liu M, Zhang Y, Zhao M, Li Z, Wu C, Qiao Y, Yang J, Wang X, Zhang L, Li M, Zhou X. STAT3/HOTAIR signaling Axis regulates HNSCC growth in an EZH2-dependent manner. Clin Cancer Res. 2018;24:2665–77.PubMedCrossRef
82.
Ding J, Yeh CR, Sun Y, Lin C, Chou J, Ou Z, Chang C, Qi J, Yeh S. Estrogen receptor beta promotes renal cell carcinoma progression via regulating LncRNA HOTAIR-miR-138/200c/204/217 associated CeRNA network. Oncogene. 2018;37:5037–53.PubMedCrossRef
83.
Yan Y, Han J, Li Z, Yang H, Sui Y, Wang M. Elevated RNA expression of long noncoding HOTAIR promotes cell proliferation and predicts a poor prognosis in patients with diffuse large B cell lymphoma. Mol Med Rep. 2016;13:5125–31.PubMedPubMedCentralCrossRef
84.
Oh EJ, Kim SH, Yang WI, Ko YH, Yoon SO. Long non-coding RNA HOTAIR expression in diffuse large B-cell lymphoma: in relation to Polycomb repressive complex pathway proteins and H3K27 trimethylation. J Pathol Transl Med. 2016;50:369–76.PubMedPubMedCentralCrossRef
85.
Chen M, Xia Z, Chen C, Hu W, Yuan Y. LncRNA MALAT1 promotes epithelial-to-mesenchymal transition of esophageal cancer through Ezh2-Notch1 signaling pathway. Anti-Cancer Drugs. 2018;29:767–73.PubMed
86.
Huo Y, Li Q, Wang X, Jiao X, Zheng J, Li Z, Pan X. MALAT1 predicts poor survival in osteosarcoma patients and promotes cell metastasis through associating with EZH2. Oncotarget. 2017;8:46993–7006.PubMedPubMedCentral
87.
Han T, Jiao F, Hu H, Yuan C, Wang L, Jin ZL, Song WF, Wang LW. EZH2 promotes cell migration and invasion but not alters cell proliferation by suppressing E-cadherin, partly through association with MALAT-1 in pancreatic cancer. Oncotarget. 2016;7:11194–207.PubMedPubMedCentral
88.
Wang D, Ding L, Wang L, Zhao Y, Sun Z, Karnes RJ, Zhang J, Huang H. LncRNA MALAT1 enhances oncogenic activities of EZH2 in castration-resistant prostate cancer. Oncotarget. 2015;6:41045–55.PubMedPubMedCentral
89.
Li P, Zhang X, Wang H, Wang L, Liu T, Du L, Yang Y, Wang C. MALAT1 is associated with poor response to oxaliplatin-based chemotherapy in colorectal cancer patients and promotes chemoresistance through EZH2. Mol Cancer Ther. 2017;16:739–51.PubMedCrossRef
90.
Wang X, Sehgal L, Jain N, Khashab T, Mathur R, Samaniego F. LncRNA MALAT1 promotes development of mantle cell lymphoma by associating with EZH2. J Transl Med. 2016;14:346.PubMedPubMedCentralCrossRef
91.
Kim SH, Kim SH, Yang WI, Kim SJ, Yoon SO. Association of the long non-coding RNA MALAT1 with the polycomb repressive complex pathway in T and NK cell lymphoma. Oncotarget. 2017;8:31305–17.PubMedPubMedCentral
92.
Kangarlouei R, Irani S, Noormohammadi Z, Memari F, Mirfakhraie R. ANRIL and ANRASSF1 long noncoding RNAs are upregulated in gastric cancer. J Cell Biochem. 2019;120:12544–8.PubMedCrossRef
93.
Chen F, Li M, Zhu X. Propofol suppresses proliferation and migration of papillary thyroid cancer cells by down-regulation of lncRNA ANRIL. Exp Mol Pathol. 2019;107:68–76.PubMedCrossRef
94.
Yang Y, Peng XW. The silencing of long non-coding RNA ANRIL suppresses invasion, and promotes apoptosis of retinoblastoma cells through the ATM-E2F1 signaling pathway. Biosci Rep. 2018;38.
95.
Sun LY, Li XJ, Sun YM, Huang W, Fang K, Han C, Chen ZH, Luo XQ, Chen YQ, Wang WT. LncRNA ANRIL regulates AML development through modulating the glucose metabolism pathway of AdipoR1/AMPK/SIRT1. Mol Cancer. 2018;17:127.PubMedPubMedCentralCrossRef
96.
Song Z, Wu W, Chen M, Cheng W, Yu J, Fang J, Xu L, Yasunaga JI, Matsuoka M, Zhao T. Long noncoding RNA ANRIL supports proliferation of adult T-cell leukemia cells through cooperation with EZH2. J Virology. 2018;92:e00909–18.PubMedPubMedCentral
97.
Kikuchi J, Koyama D, Wada T, Izumi T, Hofgaard PO, Bogen B, Furukawa Y. Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma. J Clin Invest. 2015;125:4375–90.PubMedPubMedCentralCrossRef
98.
Kaneko S, Li G, Son J, Xu CF, Margueron R, Neubert TA, Reinberg D. Phosphorylation of the PRC2 component Ezh2 is cell cycle-regulated and up-regulates its binding to ncRNA. Genes Dev. 2010;24:2615–20.PubMedPubMedCentralCrossRef
99.
Wei Y, Chen YH, Li LY, Lang J, Yeh SP, Shi B, Yang CC, Yang JY, Lin CY, Lai CC, Hung MC. CDK1-dependent phosphorylation of EZH2 suppresses methylation of H3K27 and promotes osteogenic differentiation of human mesenchymal stem cells. Nat Cell Biol. 2011;13:87–94.PubMedCrossRef
100.
Wu SC, Zhang Y. Cyclin-dependent kinase 1 (CDK1)-mediated phosphorylation of enhancer of zeste 2 (Ezh2) regulates its stability. J Biol Chem. 2011;286:28511–9.PubMedPubMedCentralCrossRef
101.
Oh EJ, Kim EK, Yang WI, Yoon SO. Activation of the polycomb repressive complex pathway in the bone marrow resident cells of diffuse large B-cell lymphoma patients. Leukemia Lymphoma. 2016;57:1921–32.PubMedCrossRef
102.
Yi S, Sun J, Qiu L, Fu W, Wang A, Liu X, Yang Y, Kadin ME, Tu P, Wang Y. Dual role of EZH2 in cutaneous anaplastic large cell lymphoma: promoting tumor cell survival and regulating tumor microenvironment. J Invest Dermatol. 2018;138:1126–36.PubMedCrossRef
103.
Ennishi D, Takata K, Beguelin W, Duns G, Mottok A, Farinha P, Bashashati A, Saberi S, Boyle M, Meissner B, Ben-Neriah S, Woolcock BW, Telenius A, Lai D, Teater M, Kridel R, Savage KJ, Sehn LH, Morin RD, Marra MA, Shah SP, Connors JM, Gascoyne RD, Scott DW, Melnick AM, Steidl C. Molecular and genetic characterization of MHC deficiency identifies EZH2 as therapeutic target for enhancing immune recognition. Cancer Dis. 2019;9:546–63.CrossRef
104.
Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from burkitt’s lymphoma. Lancet. 1964;1:702–3.PubMedCrossRef
105.
Shannon-Lowe C, Rickinson AB, Bell AI. Epstein-Barr virus-associated lymphomas, philosophical transactions of the Royal Society of London. Series B. Biol Sci. 2017;372.
106.
107.
Murata T, Kondo Y, Sugimoto A, Kawashima D, Saito S, Isomura H, Kanda T, Tsurumi T. Epigenetic histone modification of Epstein-Barr virus BZLF1 promoter during latency and reactivation in Raji cells. J Virol. 2012;86:4752–61.PubMedPubMedCentralCrossRef
108.
Siouda M, Frecha C, Accardi R, Yue J, Cuenin C, Gruffat H, Manet E, Herceg Z, Sylla BS, Tommasino M. Epstein-Barr virus down-regulates tumor suppressor DOK1 expression. PLoS Pathog. 2014;10:e1004125.PubMedPubMedCentralCrossRef
109.
Accardi R, Fathallah I, Gruffat H, Mariggio G, Le Calvez-Kelm F, Voegele C, Bartosch B, Hernandez-Vargas H, McKay J, Sylla BS, Manet E, Tommasino M. Epstein - Barr virus transforming protein LMP-1 alters B cells gene expression by promoting accumulation of the oncoprotein DeltaNp73alpha. PLoS Pathog. 2013;9:e1003186.PubMedPubMedCentralCrossRef
110.
Jiang S, Zhou H, Liang J, Gerdt C, Wang C, Ke L, Schmidt SCS, Narita Y, Ma Y, Wang S, Colson T, Gewurz B, Li G, Kieff E, Zhao B. The Epstein-Barr virus regulome in lymphoblastoid cells. Cell Host Microbe. 2017;22:561–573.e564.PubMedPubMedCentralCrossRef
111.
Wood CD, Veenstra H, Khasnis S, Gunnell A, Webb HM, Shannon-Lowe C, Andrews S, Osborne CS, West MJ. MYC activation and BCL2L11 silencing by a tumour virus through the large-scale reconfiguration of enhancer-promoter hubs. eLife. 2016;5:e18270.PubMedPubMedCentralCrossRef
112.
de Oliveira DE, Ballon G, Cesarman E. NF-kappaB signaling modulation by EBV and KSHV. Trends Microbiol. 2010;18:248–57.PubMedCrossRef
113.
Mayers DL, Mikovits JA, Joshi B, Hewlett IK, Estrada JS, Wolfe AD, Garcia GE, Doctor BP, Burke DS, Gordon RK, et al. Anti-human immunodeficiency virus 1 (HIV-1) activities of 3-deazaadenosine analogs: increased potency against 3′-azido-3′-deoxythymidine-resistant HIV-1 strains. Proc Natl Acad Sci U S A. 1995;92:215–9.PubMedPubMedCentralCrossRef
114.
Gordon RK, Ginalski K, Rudnicki WR, Rychlewski L, Pankaskie MC, Bujnicki JM, Chiang PK. Anti-HIV-1 activity of 3-deaza-adenosine analogs. Inhibition of S-adenosylhomocysteine hydrolase and nucleotide congeners. Eur J Biochem. 2003;270:3507–17.PubMedCrossRef
115.
Tan J, Yang X, Zhuang L, Jiang X, Chen W, Lee PL, Karuturi RK, Tan PB, Liu ET, Yu Q. Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev. 2007;21:1050–63.PubMedPubMedCentralCrossRef
116.
Rao M, Chinnasamy N, Hong JA, Zhang Y, Zhang M, Xi S, Liu F, Marquez VE, Morgan RA, Schrump DS. Inhibition of histone lysine methylation enhances cancer-testis antigen expression in lung cancer cells: implications for adoptive immunotherapy of cancer. Cancer Res. 2011;71:4192–204.PubMedPubMedCentralCrossRef
117.
Fiskus W, Wang Y, Sreekumar A, Buckley KM, Shi H, Jillella A, Ustun C, Rao R, Fernandez P, Chen J, Balusu R, Koul S, Atadja P, Marquez VE, Bhalla KN. Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells. Blood. 2009;114:2733–43.PubMedPubMedCentralCrossRef
118.
Crea F, Hurt EM, Mathews LA, Cabarcas SM, Sun L, Marquez VE, Danesi R, Farrar WL. Pharmacologic disruption of polycomb repressive complex 2 inhibits tumorigenicity and tumor progression in prostate cancer. Mol Cancer. 2011;10:40.PubMedPubMedCentralCrossRef
119.
Bouzelfen A, Kora H, Alcantara M, Bertrand P, Latouche JB, Jardin F. Heterogeneous epigenetic regulation of HACE1 in Burkitt- lymphoma-derived cells. Leukemia Res. 2017;60:53–7.CrossRef
120.
Shen J, Su J, Wu D, Zhang F, Fu H, Zhou H, Xu M. Growth inhibition accompanied by MOB1 upregulation in human acute lymphoid leukemia cells by 3-deazaneplanocin a. Biochem Genet. 2015;53:268–79.PubMedCrossRef
121.
Miranda TB, Cortez CC, Yoo CB, Liang G, Abe M, Kelly TK, Marquez VE, Jones PA. DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation. Mol Cancer Ther. 2009;8:1579–88.PubMedPubMedCentralCrossRef
122.
Xu L, Tang H, Wang K, Zheng Y, Feng J, Dong H, Jin Y, Cao C, Chen X, Gao G. Pharmacological inhibition of EZH2 combined with DNAdamaging agents interferes with the DNA damage response in MM cells. Mol Med Rep. 2019;19:4249–55.PubMedPubMedCentral
123.
Lue JK, Prabhu SA, Liu Y, Gonzalez Y, Verma A, Mundi PS, Abshiru N, Camarillo JM, Mehta S, Chen EI, Qiao C, Nandakumar R, Cremers S, Kelleher NL, Elemento O, Amengual JE. Precision targeting with EZH2 and HDAC inhibitors in epigenetically dysregulated lymphomas. Clin Cancer Res. 2019.
124.
Adamik J, Jin S, Sun Q, Zhang P, Weiss KR, Anderson JL, Silbermann R, Roodman GD, Galson DL. EZH2 or HDAC1 inhibition reverses multiple myeloma-induced epigenetic suppression of osteoblast differentiation. Mol Cancer Res. 2017;15:405–17.PubMedPubMedCentralCrossRef
125.
Zeng D, Liu M, Pan J. Blocking EZH2 methylation transferase activity by GSK126 decreases stem cell-like myeloma cells. Oncotarget. 2017;8:3396–411.PubMed
126.
Ott HM, Graves AP, Pappalardi MB, Huddleston M, Halsey WS, Hughes AM, Groy A, Dul E, Jiang Y, Bai Y, Annan R, Verma SK, Knight SD, Kruger RG, Dhanak D, Schwartz B, Tummino PJ, Creasy CL, McCabe MT. A687V EZH2 is a driver of histone H3 lysine 27 (H3K27) hypertrimethylation. Mol Cancer Ther. 2014;13:3062–73.PubMedCrossRef
127.
Ezponda T, Dupere-Richer D, Will CM, Small EC, Varghese N, Patel T, Nabet B, Popovic R, Oyer J, Bulic M, Zheng Y, Huang X, Shah MY, Maji S, Riva A, Occhionorelli M, Tonon G, Kelleher N, Keats J, Licht JD. UTX/KDM6A loss enhances the malignant phenotype of multiple myeloma and sensitizes cells to EZH2 inhibition. Cell Rep. 2017;21:628–40.PubMedPubMedCentralCrossRef
128.
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. Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc Natl Acad Sci U S A. 2012;109:21360–5.PubMedPubMedCentralCrossRef
129.
Herviou L, Kassambara A, Boireau S, Robert N, Requirand G, Muller-Tidow C, Vincent L, Seckinger A, Goldschmidt H, Cartron G, Hose D, Cavalli G, Moreaux J. PRC2 targeting is a therapeutic strategy for EZ score defined high-risk multiple myeloma patients and overcome resistance to IMiDs. Clin Epigenetics. 2018;10:121.PubMedPubMedCentralCrossRef
130.
Dimopoulos K, Sogaard Helbo A, Fibiger Munch-Petersen H, Sjo L, Christensen J, Sommer Kristensen L, Asmar F, Hermansen NEU, O'Connel C, Gimsing P, Liang G, Gronbaek K. Dual inhibition of DNMTs and EZH2 can overcome both intrinsic and acquired resistance of myeloma cells to IMiDs in a cereblon-independent manner. Mol Oncol. 2018;12:180–95.PubMedCrossRef
131.
Brach D, Johnston-Blackwell D, Drew A, Lingaraj T, Motwani V, Warholic NM, Feldman I, Plescia C, Smith JJ, Copeland RA, Keilhack H, Chan-Penebre E, Knutson SK, Ribich SA, Raimondi A, Thomenius MJ. EZH2 inhibition by Tazemetostat results in altered dependency on B-cell activation signaling in DLBCL. Mol Cancer Ther. 2017;16:2586–97.PubMedCrossRef
132.
Knutson SK, Kawano S, Minoshima Y, Warholic NM, Huang KC, Xiao Y, Kadowaki T, Uesugi M, Kuznetsov G, Kumar N, Wigle TJ, Klaus CR, Allain CJ, Raimondi A, Waters NJ, Smith JJ, Porter-Scott M, Chesworth R, Moyer MP, Copeland RA, Richon VM, Uenaka T, Pollock RM, Kuntz KW, Yokoi A, Keilhack H. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol Cancer Ther. 2014;13:842–54.PubMedCrossRef
133.
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. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol. 2012;8:890–6.PubMedCrossRef
134.
Campbell JE, Kuntz KW, Knutson SK, Warholic NM, Keilhack H, Wigle TJ, Raimondi A, Klaus CR, Rioux N, Yokoi A, Kawano S, Minoshima Y, Choi HW, Porter Scott M, Waters NJ, Smith JJ, Chesworth R, Moyer MP, Copeland RA. EPZ011989, a potent, orally-available EZH2 inhibitor with robust in vivo activity. ACS Med Chem Lett. 2015;6:491–5.PubMedPubMedCentralCrossRef
135.
Lu B, Shen X, Zhang L, Liu D, Zhang C, Cao J, Shen R, Zhang J, Wang D, Wan H, Xu Z, Ho MH, Zhang M, Zhang L, He F, Tao W. Discovery of EBI-2511: a highly potent and orally active EZH2 inhibitor for the treatment of non-Hodgkin's lymphoma. ACS Med Chem Lett. 2018;9:98–102.PubMedPubMedCentralCrossRef
136.
Song X, Zhang L, Gao T, Ye T, Zhu Y, Lei Q, Feng Q, He B, Deng H, Yu L. Selective inhibition of EZH2 by ZLD10A blocks H3K27 methylation and kills mutant lymphoma cells proliferation. Biomed Pharmacother. 2016;81:288–94.PubMedCrossRef
137.
Wu Y, Hu J, Ding H, Chen L, Zhang Y, Liu R, Xu P, Du D, Lu W, Liu J, Liu Y, Liu YC, Lu J, Zhang J, Yao Z, Luo C. Identification of novel EZH2 inhibitors through pharmacophore-based virtual screening and biological assays. Bioorg Med Chem Lett. 2016;26:3813–7.PubMedCrossRef
138.
Vaswani RG, Gehling VS, Dakin LA, Cook AS, Nasveschuk CG, Duplessis M, Iyer P, Balasubramanian S, Zhao F, Good AC, Campbell R, Lee C, Cantone N, Cummings RT, Normant E, Bellon SF, Albrecht BK, Harmange JC, Trojer P, Audia JE, Zhang Y, Justin N, Chen S, Wilson JR, Gamblin SJ. Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1 -(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a potent and selective inhibitor of histone methyltransferase EZH2, suitable for phase I clinical trials for B-cell lymphomas. J Med chemistry. 2016;59:9928–41.CrossRef
139.
Nasveschuk CG, Gagnon A, Garapaty-Rao S, Balasubramanian S, Campbell R, Lee C, Zhao F, Bergeron L, Cummings R, Trojer P, Audia JE, Albrecht BK, Harmange JC. Discovery and optimization of Tetramethylpiperidinyl Benzamides as inhibitors of EZH2. ACS Med Chem Lett. 2014;5:378–83.PubMedPubMedCentralCrossRef
140.
Verma SK, Tian X, LaFrance LV, Duquenne C, Suarez DP, Newlander KA, Romeril SP, Burgess JL, Grant SW, Brackley JA, Graves AP, Scherzer DA, Shu A, Thompson C, Ott HM, Aller GS, Machutta CA, Diaz E, Jiang Y, Johnson NW, Knight SD, Kruger RG, McCabe MT, Dhanak D, Tummino PJ, Creasy CL, Miller WH. Identification of potent, selective, cell-active inhibitors of the histone lysine methyltransferase EZH2. ACS Med Chem Lett. 2012;3:1091–6.PubMedPubMedCentralCrossRef
141.
Italiano A, Soria JC, Toulmonde M, Michot JM, Lucchesi C, Varga A, Coindre JM, Blakemore SJ, Clawson A, Suttle B, McDonald AA, Woodruff M, Ribich S, Hedrick E, Keilhack H, Thomson B, Owa T, Copeland RA, Ho PTC, Ribrag V. 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. 2018;19:649–59.PubMedCrossRef
142.
Konze KD, Ma A, Li F, Barsyte-Lovejoy D, Parton T, Macnevin CJ, Liu F, Gao C, Huang XP, Kuznetsova E, Rougie M, Jiang A, Pattenden SG, Norris JL, James LI, Roth BL, Brown PJ, Frye SV, Arrowsmith CH, Hahn KM, Wang GG, Vedadi M, Jin J. An orally bioavailable chemical probe of the lysine methyltransferases EZH2 and EZH1. ACS Chem Biol. 2013;8:1324–34.PubMedPubMedCentralCrossRef
143.
Garapaty-Rao S, Nasveschuk C, Gagnon A, Chan EY, Sandy P, Busby J, Balasubramanian S, Campbell R, Zhao F, Bergeron L, Audia JE, Albrecht BK, Harmange JC, Cummings R, Trojer P. Identification of EZH2 and EZH1 small molecule inhibitors with selective impact on diffuse large B cell lymphoma cell growth. Chem Biol. 2013;20:1329–39.PubMedCrossRef
144.
Woo J, Kim HY, Byun BJ, Chae CH, Lee JY, Ryu SY, Park WK, Cho H, Choi G. Biological evaluation of tanshindiols as EZH2 histone methyltransferase inhibitors. Bioorg Med Chem Lett. 2014;24:2486–92.PubMedCrossRef
145.
146.
Huang X, Yan J, Zhang M, Wang Y, Chen Y, Fu X, Wei R, Zheng XL, Liu Z, Zhang X, Yang H, Hao B, Shen YY, Su Y, Cong X, Huang M, Tan M, Ding J, Geng M. Targeting epigenetic crosstalk as a therapeutic strategy for EZH2-aberrant solid tumors. Cell. 2018;175:186–199.e119.PubMedCrossRef
147.
Gibaja V, Shen F, Harari J, Korn J, Ruddy D, Saenz-Vash V, Zhai H, Rejtar T, Paris CG, Yu Z, Lira M, King D, Qi W, Keen N, Hassan AQ, Chan HM. Development of secondary mutations in wild-type and mutant EZH2 alleles cooperates to confer resistance to EZH2 inhibitors. Oncogene. 2016;35:558–66.PubMedCrossRef
148.
Baker T, Nerle S, Pritchard J, Zhao B, Rivera VM, Garner A, Gonzalvez F. Acquisition of a single EZH2 D1 domain mutation confers acquired resistance to EZH2-targeted inhibitors. Oncotarget. 2015;6:32646–55.PubMedPubMedCentralCrossRef
149.
Kim W, Bird GH, Neff T, Guo G, Kerenyi MA, Walensky LD, Orkin SH. Targeted disruption of the EZH2-EED complex inhibits EZH2-dependent cancer. Nat Chem Biol. 2013;9:643–50.PubMedPubMedCentralCrossRef
150.
Kong X, Chen L, Jiao L, Jiang X, Lian F, Lu J, Zhu K, Du D, Liu J, Ding H, Zhang N, Shen J, Zheng M, Chen K, Liu X, Jiang H, Luo C. Astemizole arrests the proliferation of cancer cells by disrupting the EZH2-EED interaction of polycomb repressive complex 2. J Med Chem. 2014;57:9512–21.PubMedCrossRef
151.
Li L, Zhang H, Zhang M, Zhao M, Feng L, Luo X, Gao Z, Huang Y, Ardayfio O, Zhang JH, Lin Y, Fan H, Mi Y, Li G, Liu L, Feng L, Luo F, Teng L, Qi W, Ottl J, Lingel A, Bussiere DE, Yu Z, Atadja P, Lu C, Li E, Gu J, Zhao K. Discovery and molecular basis of a diverse set of Polycomb repressive complex 2 inhibitors recognition by EED. PLoS One. 2017;12:e0169855.PubMedPubMedCentralCrossRef
152.
Huang Y, Zhang J, Yu Z, Zhang H, Wang Y, Lingel A, Qi W, Gu J, Zhao K, Shultz MD, Wang L, Fu X, Sun Y, Zhang Q, Jiang X, Zhang J, Zhang C, Li L, Zeng J, Feng L, Zhang C, Liu Y, Zhang M, Zhang L, Zhao M, Gao Z, Liu X, Fang D, Guo H, Mi Y, Gabriel T, Dillon MP, Atadja P, Oyang C. Discovery of first-in-class, potent, and orally bioavailable embryonic ectoderm development (EED) inhibitor with robust anticancer efficacy. J Med Chem. 2017;60:2215–26.PubMedCrossRef
153.
Qi W, Zhao K, Gu J, Huang Y, Wang Y, Zhang H, Zhang M, Zhang J, Yu Z, Li L, Teng L, Chuai S, Zhang C, Zhao M, Chan H, Chen Z, Fang D, Fei Q, Feng L, Feng L, Gao Y, Ge H, Ge X, Li G, Lingel A, Lin Y, Liu Y, Luo F, Shi M, Wang L, Wang Z, Yu Y, Zeng J, Zeng C, Zhang L, Zhang Q, Zhou S, Oyang C, Atadja P, Li E. An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED. Nat Chem Biol. 2017;13:381–8.PubMedCrossRef
154.
Rizq O, Mimura N, Oshima M, Saraya A, Koide S, Kato Y, Aoyama K, Nakajima-Takagi Y, Wang C, Chiba T, Ma A, Jin J, Iseki T, Nakaseko C, Iwama A. Dual inhibition of EZH2 and EZH1 sensitizes PRC2-dependent tumors to proteasome inhibition. Clin Cancer Res. 2017;23:4817–30.PubMedPubMedCentralCrossRef
155.
Smonskey M, Lasorsa E, Rosario S, Kirk JS, Hernandez-Ilizaliturri FJ, Ellis L. EZH2 inhibition re-sensitizes multidrug resistant B-cell lymphomas to etoposide mediated apoptosis. Oncoscience. 2016;3:21–30.PubMedPubMedCentral
156.
D’Angelo V, Iannotta A, Ramaglia M, Lombardi A, Zarone MR, Desiderio V, Affinita MC, Pecoraro G, Di Martino M, Indolfi P, Casale F, Caraglia M. EZH2 is increased in paediatric T-cell acute lymphoblastic leukemia and is a suitable molecular target in combination treatment approaches. J Exp Clin Cancer Res. 2015;34:83.PubMedPubMedCentralCrossRef
157.
Harding T, Swanson J, Van Ness B. EZH2 inhibitors sensitize myeloma cell lines to panobinostat resulting in unique combinatorial transcriptomic changes. Oncotarget. 2018;9:21930–42.PubMedPubMedCentralCrossRef
158.
Kalushkova A, Fryknas M, Lemaire M, Fristedt C, Agarwal P, Eriksson M, Deleu S, Atadja P, Osterborg A, Nilsson K, Vanderkerken K, Oberg F, Jernberg-Wiklund H. Polycomb target genes are silenced in multiple myeloma. PLoS One. 2010;5:e11483.PubMedPubMedCentralCrossRef
159.
Fiskus W, Rao R, Balusu R, Ganguly S, Tao J, Sotomayor E, Mudunuru U, Smith JE, Hembruff SL, Atadja P, Marquez VE, Bhalla K. Superior efficacy of a combined epigenetic therapy against human mantle cell lymphoma cells. Clin Cancer Res. 2012;18:6227–38.PubMedPubMedCentralCrossRef
160.
Johnson DP, Spitz GS, Tharkar S, Quayle SN, Shearstone JR, Jones S, McDowell ME, Wellman H, Tyler JK, Cairns BR, Chandrasekharan MB, Bhaskara S. HDAC1,2 inhibition impairs EZH2- and BBAP-mediated DNA repair to overcome chemoresistance in EZH2 gain-of-function mutant diffuse large B-cell lymphoma. Oncotarget. 2015;6:4863–87.PubMed
161.
Huang S, Wang Z, Zhou J, Huang J, Zhou L, Luo J, Wan YY, Long H, Zhu B. EZH2 inhibitor GSK126 suppresses antitumor immunity by driving production of myeloid-derived suppressor cells. Cancer Res. 2019;79:2009–20.PubMedCrossRef
Metadata
Title
EZH2 abnormalities in lymphoid malignancies: underlying mechanisms and therapeutic implications
Authors
Boheng Li
Wee-Joo Chng
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2019
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-019-0814-6

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