Epigenetic regulation of cancer biology and anti-tumor immunity by EZH2

Oncotarget

Volumn 7, Issue 51, 2016, Pages 85624-85640

  Christofides, Anthos ^a,b   Karantanos, Theodoros ^a,b,c   Bardhan, Kankana ^a,b   Boussiotis, Vassiliki A ^a,b  

^a BETH ISRAEL DEACONESS MEDICAL CENTER   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

^c BOSTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Cancer biology; Cancer immunology; Epigenetics; EZH2

Indexed keywords

BMI1 PROTEIN; HISTONE H2A; HISTONE H3; POLYCOMB REPRESSIVE COMPLEX 2; TRANSCRIPTION FACTOR EZH2; ANTINEOPLASTIC AGENT; EZH2 PROTEIN, HUMAN;

APOPTOSIS; CANCER IMMUNOTHERAPY; CARCINOGENESIS; CELL CYCLE PROGRESSION; CELL DIFFERENTIATION; CELL PROLIFERATION; CHROMATIN; CHROMATIN MODULATION; CHROMATIN STRUCTURE; EFFECTOR CELL; EPIGENETICS; EPITHELIAL MESENCHYMAL TRANSITION; EZH2 GENE; GENE EXPRESSION; GENE MUTATION; GENETIC REGULATION; HISTONE UBIQUITINATION; HUMAN; INTRACELLULAR SIGNALING; LEUKEMIA; NONHODGKIN LYMPHOMA; NONHUMAN; PROTEIN FUNCTION; PROTEIN PROCESSING; REGULATORY T LYMPHOCYTE; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; SOLID TUMOR; TRANSCRIPTION REGULATION; TUMOR IMMUNITY; ANIMAL; ANTAGONISTS AND INHIBITORS; CHROMATIN ASSEMBLY AND DISASSEMBLY; DNA METHYLATION; DRUG EFFECTS; ENZYMOLOGY; GENE EXPRESSION REGULATION; GENETIC EPIGENESIS; GENETICS; IMMUNOLOGY; METABOLISM; MOLECULARLY TARGETED THERAPY; NEOPLASM; SIGNAL TRANSDUCTION; TUMOR ESCAPE;

ANIMALS; ANTINEOPLASTIC AGENTS; CHROMATIN ASSEMBLY AND DISASSEMBLY; DNA METHYLATION; ENHANCER OF ZESTE HOMOLOG 2 PROTEIN; EPIGENESIS, GENETIC; GENE EXPRESSION REGULATION, ENZYMOLOGIC; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; MOLECULAR TARGETED THERAPY; NEOPLASMS; SIGNAL TRANSDUCTION; TUMOR ESCAPE;

EID: 85007480266     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.12928     Document Type: Review

References (133)

1. Lewis EB. A gene complex controlling segmentation in Drosophila. Nature. 1978; 276(5688):565-570.
2. Margueron R and Reinberg D. The Polycomb complex PRC2 and its mark in life. Nature. 2011; 469(7330):343-349.
3. Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones RS and Zhang Y. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science (New York, NY). 2002; 298(5595):1039-1043.
4. Ku M, Koche RP, Rheinbay E, Mendenhall EM, Endoh M, Mikkelsen TS, Presser A, Nusbaum C, Xie X, Chi AS, Adli M, Kasif S, Ptaszek LM, et al. Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains. PLoS genetics. 2008; 4(10):e1000242.
5. Gui Y, Guo G, Huang Y, Hu X, Tang A, Gao S, Wu R, Chen C, Li X, Zhou L, He M, Li Z, Sun X, et al. Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nature genetics. 2011; 43(9):875-878.
6. Ho AS, Kannan K, Roy DM, Morris LG, Ganly I, Katabi N, Ramaswami D, Walsh LA, Eng S, Huse JT, Zhang J, Dolgalev I, Huberman K, et al. The mutational landscape of adenoid cystic carcinoma. Nature genetics. 2013; 45(7):791-798.
7. Huether R, Dong L, Chen X, Wu G, Parker M, Wei L, Ma J, Edmonson MN, Hedlund EK, Rusch MC, Shurtleff SA, Mulder HL, Boggs K, et al. The landscape of somatic mutations in epigenetic regulators across 1, 000 paediatric cancer genomes. Nature communications. 2014; 5:3630.
8. Orkin SH and Hochedlinger K. Chromatin connections to pluripotency and cellular reprogramming. Cell. 2011; 145(6):835-850.
9. Wu L, Murat P, Matak-Vinkovic D, Murrell A and Balasubramanian S. Binding interactions between long noncoding RNA HOTAIR and PRC2 proteins. Biochemistry. 2013; 52(52):9519-9527.
10. Kim KH and Roberts CW. Targeting EZH2 in cancer. Nature medicine. 2016; 22(2):128-134.
11. Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, Ghosh D, Pienta KJ, Sewalt RG, Otte AP, Rubin MA and Chinnaiyan AM. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002; 419(6907):624-629.
12. Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, Ghosh D, Sewalt RG, Otte AP, Hayes DF, Sabel MS, Livant D, Weiss SJ, et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proceedings of the National Academy of Sciences of the United States of America. 2003; 100(20):11606-11611.
13. Lee HW and Choe M. Expression of EZH2 in renal cell carcinoma as a novel prognostic marker. Pathology international. 2012; 62(11):735-741.
14. Behrens C, Solis LM, Lin H, Yuan P, Tang X, Kadara H, Riquelme E, Galindo H, Moran CA, Kalhor N, Swisher SG, Simon GR, Stewart DJ, et al. EZH2 protein expression associates with the early pathogenesis, tumor progression, and prognosis of non-small cell lung carcinoma. Clinical cancer research. 2013; 19(23):6556-6565.
15. Sato T, Kaneda A, Tsuji S, Isagawa T, Yamamoto S, Fujita T, Yamanaka R, Tanaka Y, Nukiwa T, Marquez VE, Ishikawa Y, Ichinose M and Aburatani H. PRC2 overexpression and PRC2-target gene repression relating to poorer prognosis in small cell lung cancer. Scientific reports. 2013; 3:1911.
16. Kondo Y, Shen L, Suzuki S, Kurokawa T, Masuko K, Tanaka Y, Kato H, Mizuno Y, Yokoe M, Sugauchi F, Hirashima N, Orito E, Osada H, et al. Alterations of DNA methylation and histone modifications contribute to gene silencing in hepatocellular carcinomas. Hepatology research. 2007; 37(11):974-983.
17. Matsukawa Y, Semba S, Kato H, Ito A, Yanagihara K and Yokozaki H. Expression of the enhancer of zeste homolog 2 is correlated with poor prognosis in human gastric cancer. Cancer science. 2006; 97(6):484-491.
18. Ougolkov AV, Bilim VN and Billadeau DD. Regulation of pancreatic tumor cell proliferation and chemoresistance by the histone methyltransferase enhancer of zeste homologue 2. Clinical cancer research. 2008; 14(21):6790-6796.
19. Wang X, Zhao H, Lv L, Bao L, Wang X and Han S. Prognostic Significance of EZH2 Expression in Non-Small Cell Lung Cancer: A Meta-analysis. Scientific reports. 2016; 6:19239.
20. Bachmann IM, Halvorsen OJ, Collett K, Stefansson IM, Straume O, Haukaas SA, Salvesen HB, Otte AP and Akslen LA. EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. Journal of clinical oncology. 2006; 24(2):268-273.
21. Song-Bing H, Hao Z, Jian Z, Guo-Qiang Z, Tuo H, Dai-Wei W, Wen G, Lin G, Yi Z, Xiao-Feng X, Li-Feng Z, Min F, Shui-Qing H, et al. Inhibition of EZH2 expression is associated with the proliferation, apoptosis and migration of SW620 colorectal cancer cells in vitro. Experimental biology and medicine (Maywood, NJ). 2015; 240(4):546-555.
22. Wang W, Wang F, Zong G, Liu R, Zhang Y, Luan Y, Xu L and Xuan J. Prognostic significance of EZH2 expression in patients with digestive cancers: a meta-analysis. International journal of clinical and experimental medicine. 2015; 8(9):16043-16049.
23. Jin M, Yang Z, Ye W, Yu X and Hua X. Prognostic significance of histone methyltransferase enhancer of zeste homolog 2 in patients with cervical squamous cell carcinoma. Oncology letters. 2015; 10(2):857-862.
24. Liu F, Gu L, Cao Y, Fan X, Zhang F and Sang M. Aberrant overexpression of EZH2 and H3K27me3 serves as poor prognostic biomarker for esophageal squamous cell carcinoma patients. Biomarkers. 2016; 21(1):80-90.
25. Chang JW, Gwak SY, Shim GA, Liu L, Lim YC, Kim JM, Jung MG and Koo BS. EZH2 is associated with poor prognosis in head-and-neck squamous cell carcinoma via regulating the epithelial-to-mesenchymal transition and chemosensitivity. Oral oncology. 2016; 52:66-74.
26. Xu F, Li X, Wu L, Zhang Q, Yang R, Yang Y, Zhang Z, He Q and Chang C. Overexpression of the EZH2, RING1 and BMI1 genes is common in myelodysplastic syndromes: relation to adverse epigenetic alteration and poor prognostic scoring. Annals of hematology. 2011; 90(6):643-653.
27. Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV, Waghorn K, Zoi K, Ross FM, Reiter A, Hochhaus A, Drexler HG, Duncombe A, et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nature genetics. 2010; 42(8):722-726.
28. Nikoloski G, Langemeijer SM, Kuiper RP, Knops R, Massop M, Tonnissen ER, van der Heijden A, Scheele TN, Vandenberghe P, de Witte T, van der Reijden BA and Jansen JH. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nature genetics. 2010; 42(8):665-667.
29. Tanaka S, Miyagi S, Sashida G, Chiba T, Yuan J, Mochizuki-Kashio M, Suzuki Y, Sugano S, Nakaseko C, Yokote K, Koseki H and Iwama A. Ezh2 augments leukemogenicity by reinforcing differentiation blockage in acute myeloid leukemia. Blood. 2012; 120(5):1107-1117.
30. Sashida G, Harada H, Matsui H, Oshima M, Yui M, Harada Y, Tanaka S, Mochizuki-Kashio M, Wang C, Saraya A, Muto T, Hayashi Y, Suzuki K, et al. Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation. Nature communications. 2014; 5:4177.
31. Muto T, Sashida G, Oshima M, Wendt GR, Mochizuki-Kashio M, Nagata Y, Sanada M, Miyagi S, Saraya A, Kamio A, Nagae G, Nakaseko C, Yokote K, et al. Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders. The Journal of experimental medicine. 2013; 210(12):2627-2639.
32. Soverini S, de Benedittis C, Mancini M and Martinelli G. Mutations in the BCR-ABL1 Kinase Domain and Elsewhere in Chronic Myeloid Leukemia. Clinical lymphoma, myeloma & leukemia. 2015; 15 Suppl:S120-128.
33. Grubach L, Juhl-Christensen C, Rethmeier A, Olesen LH, Aggerholm A, Hokland P and Ostergaard M. Gene expression profiling of Polycomb, Hox and Meis genes in patients with acute myeloid leukaemia. European journal of haematology. 2008; 81(2):112-122.
34. Zhu Q, Zhang L, Li X, Chen F, Jiang L, Yu G, Wang Z, Yin C, Jiang X, Zhong Q, Zhou H, Ding B, Wang C, et al. Higher EZH2 expression is associated with extramedullary infiltration in acute myeloid leukemia. Tumour biology. 2016.
35. 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, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nature genetics. 2010; 42(2):181-185.
36. Bodor C, O'Riain C, Wrench D, Matthews J, Iyengar S, Tayyib H, Calaminici M, Clear A, Iqbal S, Quentmeier H, Drexler HG, Montoto S, Lister AT, et al. EZH2 Y641 mutations in follicular lymphoma. Leukemia. 2011; 25(4):726-729.
37. 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, et al. Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis. The Journal of clinical investigation. 2013; 123(12):5009-5022.
38. 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, et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nature chemical biology. 2012; 8(11):890-896.
39. McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS, Liu Y, Graves AP, Della Pietra A, 3rd, Diaz E, LaFrance LV, Mellinger M, Duquenne C, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012; 492(7427):108-112.
40. 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, et al. Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proceedings of the National Academy of Sciences of the United States of America. 2012; 109(52):21360-21365.
41. Akamatsu N, Yamada Y, Hasegawa H, Makabe K, Asano R, Kumagai I, Murata K, Imaizumi Y, Tsukasaki K, Tsuruda K, Sugahara K, Atogami S, Yanagihara K, et al. High IL-21 receptor expression and apoptosis induction by IL-21 in follicular lymphoma. Cancer letters. 2007; 256(2):196-206.
42. Sarosiek KA, Malumbres R, Nechushtan H, Gentles AJ, Avisar E and Lossos IS. Novel IL-21 signaling pathway up-regulates c-Myc and induces apoptosis of diffuse large B-cell lymphomas. Blood. 2010; 115(3):570-580.
43. 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, 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(8):2451-2459.
44. Guo S, Chan JK, Iqbal J, McKeithan T, Fu K, Meng B, Pan Y, Cheuk W, Luo D, Wang R, Zhang W, Greiner TC and Chan WC. EZH2 mutations in follicular lymphoma from different ethnic groups and associated gene expression alterations. Clinical cancer research. 2014; 20(12):3078-3086.
45. 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, et al. Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proceedings of the National Academy of Sciences of the United States of America. 2012; 109(8):2989-2994.
46. Majer CR, Jin L, Scott MP, Knutson SK, Kuntz KW, Keilhack H, Smith JJ, Moyer MP, Richon VM, Copeland RA and Wigle TJ. A687V EZH2 is a gain-of-function mutation found in lymphoma patients. FEBS letters. 2012; 586(19):3448-3451.
47. Simon C, Chagraoui J, Krosl J, Gendron P, Wilhelm B, Lemieux S, Boucher G, Chagnon P, Drouin S, Lambert R, Rondeau C, Bilodeau A, Lavallee S, et al. A key role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia. Genes & development. 2012; 26(7):651-656.
48. Richter GH, Plehm S, Fasan A, Rossler S, Unland R, Bennani-Baiti IM, Hotfilder M, Lowel D, von Luettichau I, Mossbrugger I, Quintanilla-Martinez L, Kovar H, Staege MS, et al. EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuroectodermal differentiation. Proceedings of the National Academy of Sciences of the United States of America. 2009; 106(13):5324-5329.
49. Fujii S, Fukamachi K, Tsuda H, Ito K, Ito Y and Ochiai A. RAS oncogenic signal upregulates EZH2 in pancreatic cancer. Biochemical and biophysical research communications. 2012; 417(3):1074-1079.
50. Fujii S, Tokita K, Wada N, Ito K, Yamauchi C, Ito Y and Ochiai A. MEK-ERK pathway regulates EZH2 overexpression in association with aggressive breast cancer subtypes. Oncogene. 2011; 30(39):4118-4128.
51. Volkel P, Dupret B, Le Bourhis X and Angrand PO. Diverse involvement of EZH2 in cancer epigenetics. American journal of translational research. 2015; 7(2):175-193.
52. Riquelme E, Behrens C, Lin HY, Simon G, Papadimitrakopoulou V, Izzo J, Moran C, Kalhor N, Lee JJ, Minna JD and Wistuba, II. Modulation of EZH2 Expression by MEK-ERK or PI3K-AKT Signaling in Lung Cancer Is Dictated by Different KRAS Oncogene Mutations. Cancer research. 2016; 76(3):675-685.
53. Santos M, Martinez-Fernandez M, Duenas M, Garcia-Escudero R, Alfaya B, Villacampa F, Saiz-Ladera C, Costa C, Oteo M, Duarte J, Martinez V, Gomez-Rodriguez MJ, Martin ML, et al. In vivo disruption of an Rb-E2F-Ezh2 signaling loop causes bladder cancer. Cancer research. 2014; 74(22):6565-6577.
54. Coe BP, Thu KL, Aviel-Ronen S, Vucic EA, Gazdar AF, Lam S, Tsao MS and Lam WL. Genomic deregulation of the E2F/Rb pathway leads to activation of the oncogene EZH2 in small cell lung cancer. PloS one. 2013; 8(8):e71670.
55. Chang CJ, Yang JY, Xia W, Chen CT, Xie X, Chao CH, Woodward WA, Hsu JM, Hortobagyi GN and Hung MC. EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-beta-catenin signaling. Cancer cell. 2011; 19(1):86-100.
56. Dong M, Fan XJ, Chen ZH, Wang TT, Li X, Chen J, Lin Q, Wen JY, Ma XK, Wei L, Ruan DY, Lin ZX, Liu Q, et al. Aberrant expression of enhancer of zeste homologue 2, correlated with HIF-1alpha, refines relapse risk and predicts poor outcome for breast cancer. Oncology reports. 2014; 32(3):1101-1107.
57. Bohrer LR, Chen S, Hallstrom TC and Huang H. Androgens suppress EZH2 expression via retinoblastoma (RB) and p130-dependent pathways: a potential mechanism of androgen-refractory progression of prostate cancer. Endocrinology. 2010; 151(11):5136-5145.
58. Chang CJ and Hung MC. The role of EZH2 in tumour progression. British journal of cancer. 2012; 106(2):243-247.
59. Zhu Z, Tang J, Wang J, Duan G, Zhou L and Zhou X. MiR-138 Acts as a Tumor Suppressor by Targeting EZH2 and Enhances Cisplatin-Induced Apoptosis in Osteosarcoma Cells. PloS one. 2016; 11(3):e0150026.
60. Zhuang C, Wang P, Huang D, Xu L, Wang X, Wang L and Hu L. A double-negative feedback loop between EZH2 and miR-26a regulates tumor cell growth in hepatocellular carcinoma. International journal of oncology. 2016; 48(3):1195-1204.
61. Smits M, Nilsson J, Mir SE, van der Stoop PM, Hulleman E, Niers JM, de Witt Hamer PC, Marquez VE, Cloos J, Krichevsky AM, Noske DP, Tannous BA and Wurdinger T. miR-101 is down-regulated in glioblastoma resulting in EZH2-induced proliferation, migration, and angiogenesis. Oncotarget. 2010; 1(8):710-720. doi: 10.18632/oncotarget.101207.
62. Xiaoping L, Zhibin Y, Wenjuan L, Zeyou W, Gang X, Zhaohui L, Ying Z, Minghua W and Guiyuan L. CPEB1, a histone-modified hypomethylated gene, is regulated by miR-101 and involved in cell senescence in glioma. Cell death & disease. 2013; 4:e675.
63. Sharma V, Purkait S, Takkar S, Malgulwar PB, Kumar A, Pathak P, Suri V, Sharma MC, Suri A, Kale SS, Kulshreshtha R and Sarkar C. Analysis of EZH2: micro-RNA network in low and high grade astrocytic tumors. Brain tumor pathology. 2016; 33(2):117-128.
64. 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, et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science (New York, NY). 2012; 338(6113):1465-1469.
65. Kim E, Kim M, Woo DH, Shin Y, Shin J, Chang N, Oh YT, Kim H, Rheey J, Nakano I, Lee C, Joo KM, Rich JN, et al. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer cell. 2013; 23(6):839-852.
66. Kaneko S, Li G, Son J, Xu CF, Margueron R, Neubert TA and Reinberg D. Phosphorylation of the PRC2 component Ezh2 is cell cycle-regulated and up-regulates its binding to ncRNA. Genes & development. 2010; 24(23):2615-2620.
67. Wei Y, Chen YH, Li LY, Lang J, Yeh SP, Shi B, Yang CC, Yang JY, Lin CY, Lai CC and Hung MC. CDK1-dependent phosphorylation of EZH2 suppresses methylation of H3K27 and promotes osteogenic differentiation of human mesenchymal stem cells. Nature cell biology. 2011; 13(1):87-94.
68. Hussain M, Rao M, Humphries AE, Hong JA, Liu F, Yang M, Caragacianu D and Schrump DS. Tobacco smoke induces polycomb-mediated repression of Dickkopf-1 in lung cancer cells. Cancer research. 2009; 69(8):3570-3578.
69. Lee TI, Jenner RG, Boyer LA, Guenther MG, Levine SS, Kumar RM, Chevalier B, Johnstone SE, Cole MF, Isono K, Koseki H, Fuchikami T, Abe K, et al. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell. 2006; 125(2):301-313.
70. Li K, Liu C, Zhou B, Bi L, Huang H, Lin T and Xu K. Role of EZH2 in the growth of prostate cancer stem cells isolated from LNCaP cells. International journal of molecular sciences. 2013; 14(6):11981-11993.
71. Adhikary G, Grun D, Balasubramanian S, Kerr C, Huang JM and Eckert RL. Survival of skin cancer stem cells requires the Ezh2 polycomb group protein. Carcinogenesis. 2015; 36(7):800-810.
72. van Vlerken LE, Kiefer CM, Morehouse C, Li Y, Groves C, Wilson SD, Yao Y, Hollingsworth RE and Hurt EM. EZH2 is required for breast and pancreatic cancer stem cell maintenance and can be used as a functional cancer stem cell reporter. Stem cells translational medicine. 2013; 2(1):43-52.
73. Chen Q, Zheng PS and Yang WT. EZH2-mediated repression of GSK-3beta and TP53 promotes Wnt/beta-catenin signaling-dependent cell expansion in cervical carcinoma. Oncotarget. 2016; doi: 10.18632/oncotarget.8741.
74. Galvis LA, Holik AZ, Short KM, Pasquet J, Lun AT, Blewitt ME, Smyth IM, Ritchie ME and Asselin-Labat ML. Repression of Igf1 expression by Ezh2 prevents basal cell differentiation in the developing lung. Development (Cambridge, England). 2015; 142(8):1458-1469.
75. Liu T, Hou L and Huang Y. EZH2-specific microRNA-98 inhibits human ovarian cancer stem cell proliferation via regulating the pRb-E2F pathway. Tumour biology. 2014; 35(7):7239-7247.
76. Yan M, Zhang Y, He B, Xiang J, Wang ZF, Zheng FM, Xu J, Chen MY, Zhu YL, Wen HJ, Wan XB, Yue CF, Yang N, et al. IKKalpha restoration via EZH2 suppression induces nasopharyngeal carcinoma differentiation. Nature communications. 2014; 5:3661.
77. Chen JF, Luo X, Xiang LS, Li HT, Zha L, Li N, He JM, Xie GF, Xie X and Liang HJ. EZH2 promotes colorectal cancer stem-like cell expansion by activating p21cip1-Wnt/beta-catenin signaling. Oncotarget. 2016; doi: 10.18632/oncotarget.9236.
78. Zhu J, Yang DR, Sun Y, Qiu X, Chang HC, Li G, Shan Y and Chang C. TR4 Nuclear Receptor Alters the Prostate Cancer CD133+ Stem/Progenitor Cell Invasion via Modulating the EZH2-Related Metastasis Gene Expression. Molecular cancer therapeutics. 2015; 14(6):1445-1453.
79. Danis E, Yamauchi T, Echanique K, Zhang X, Haladyna JN, Riedel SS, Zhu N, Xie H, Orkin SH, Armstrong SA, Bernt KM and Neff T. Ezh2 Controls an Early Hematopoietic Program and Growth and Survival Signaling in Early T Cell Precursor Acute Lymphoblastic Leukemia. Cell reports. 2016; 14(8):1953-1965.
80. Zhang J, Chen L, Han L, Shi Z, Zhang J, Pu P and Kang C. EZH2 is a negative prognostic factor and exhibits prooncogenic activity in glioblastoma. Cancer letters. 2015; 356(2 Pt B):929-936.
81. Orlando G, Khoronenkova SV, Dianova, II, Parsons JL and Dianov GL. ARF induction in response to DNA strand breaks is regulated by PARP1. Nucleic acids research. 2014; 42(4):2320-2329.
82. Ma DN, Chai ZT, Zhu XD, Zhang N, Zhan DH, Ye BG, Wang CH, Qin CD, Zhao YM, Zhu WP, Cao MQ, Gao DM, Sun HC, et al. MicroRNA-26a suppresses epithelialmesenchymal transition in human hepatocellular carcinoma by repressing enhancer of zeste homolog 2. Journal of hematology & oncology. 2016; 9:1.
83. Cao Q, Yu J, Dhanasekaran SM, Kim JH, Mani RS, Tomlins SA, Mehra R, Laxman B, Cao X, Yu J, Kleer CG, Varambally S and Chinnaiyan AM. Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene. 2008; 27(58):7274-7284.
84. Wang J, Zhu X, Hu J, He G, Li X, Wu P, Ren X, Wang F, Liao W, Liang L and Ding Y. The positive feedback between Snail and DAB2IP regulates EMT, invasion and metastasis in colorectal cancer. Oncotarget. 2015; 6(29):27427-27439. doi: 10.18632/oncotarget.4861.
85. Smits M, van Rijn S, Hulleman E, Biesmans D, van Vuurden DG, Kool M, Haberler C, Aronica E, Vandertop WP, Noske DP and Wurdinger T. EZH2-regulated DAB2IP is a medulloblastoma tumor suppressor and a positive marker for survival. Clinical cancer research. 2012; 18(15):4048-4058.
86. Shi B, Liang J, Yang X, Wang Y, Zhao Y, Wu H, Sun L, Zhang Y, Chen Y, Li R, Zhang Y, Hong M and Shang Y. Integration of estrogen and Wnt signaling circuits by the polycomb group protein EZH2 in breast cancer cells. Molecular and cellular biology. 2007; 27(14):5105-5119.
87. Lee ST, Li Z, Wu Z, Aau M, Guan P, Karuturi RK, Liou YC and Yu Q. Context-specific regulation of NF-kappaB target gene expression by EZH2 in breast cancers. Molecular cell. 2011; 43(5):798-810.
88. Min J, Zaslavsky A, Fedele G, McLaughlin SK, Reczek EE, De Raedt T, Guney I, Strochlic DE, Macconaill LE, Beroukhim R, Bronson RT, Ryeom S, Hahn WC, et al. An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappaB. Nature medicine. 2010; 16(3):286-294.
89. Xu Z, Sun Y, Guo Y, Qin G, Mu S, Fan R, Wang B, Gao W, Wu H, Wang G and Zhang Z. NF-YA promotes invasion and angiogenesis by upregulating EZH2-STAT3 signaling in human melanoma cells. Oncology reports. 2016; 35(6):3630-3638.
90. Gunawan M, Venkatesan N, Loh JT, Wong JF, Berger H, Neo WH, Li LY, La Win MK, Yau YH, Guo T, See PC, Yamazaki S, Chin KC, et al. The methyltransferase Ezh2 controls cell adhesion and migration through direct methylation of the extranuclear regulatory protein talin. Nature immunology. 2015; 16(5):505-516.
91. Peng D, Kryczek I, Nagarsheth N, Zhao L, Wei S, Wang W, Sun Y, Zhao E, Vatan L, Szeliga W, Kotarski J, Tarkowski R, Dou Y, et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature. 2015; 527(7577):249-253.
92. Nagarsheth N, Peng D, Kryczek I, Wu K, Li W, Zhao E, Zhao L, Wei S, Frankel T, Vatan L, Szeliga W, Dou Y, Owens S, et al. PRC2 Epigenetically Silences Th1-Type Chemokines to Suppress Effector T-Cell Trafficking in Colon Cancer. Cancer research. 2016; 76(2):275-282.
93. Yin J, Leavenworth JW, Li Y, Luo Q, Xie H, Liu X, Huang S, Yan H, Fu Z, Zhang LY, Zhang L, Hao J, Wu X, et al. Ezh2 regulates differentiation and function of natural killer cells through histone methyltransferase activity. Proceedings of the National Academy of Sciences of the United States of America. 2015; 112(52):15988-15993.
94. Hayashi S, Kumai T, Matsuda Y, Aoki N, Sato K, Kimura S, Kitada M, Tateno M, Celis E and Kobayashi H. Sixtransmembrane epithelial antigen of the prostate and enhancer of zeste homolog 2 as immunotherapeutic targets for lung cancer. Journal of translational medicine. 2011; 9:191.
95. 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 and Laurence A. EZH2 is crucial for both differentiation of regulatory T cells and T effector cell expansion. Scientific reports. 2015; 5:10643.
96. Zhao E, Maj T, Kryczek I, Li W, Wu K, Zhao L, Wei S, Crespo J, Wan S, Vatan L, Szeliga W, Shao I, Wang Y, et al. Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nature immunology. 2016; 17(1):95-103.
97. DuPage M, Chopra G, Quiros J, Rosenthal WL, Morar MM, Holohan D, Zhang R, Turka L, Marson A and Bluestone JA. The chromatin-modifying enzyme Ezh2 is critical for the maintenance of regulatory T cell identity after activation. Immunity. 2015; 42(2):227-238.
98. Liu VC, Wong LY, Jang T, Shah AH, Park I, Yang X, Zhang Q, Lonning S, Teicher BA and Lee C. Tumor evasion of the immune system by converting CD4+CD25-T cells into CD4+CD25+ T regulatory cells: role of tumorderived TGF-beta. Journal of immunology (Baltimore, Md: 1950). 2007; 178(5):2883-2892.
99. Adeegbe DO and Nishikawa H. Natural and induced T regulatory cells in cancer. Frontiers in immunology. 2013; 4:190.
100. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature medicine. 2004; 10(9):942-949.
101. Viguier M, Lemaitre F, Verola O, Cho MS, Gorochov G, Dubertret L, Bachelez H, Kourilsky P and Ferradini L. Foxp3 expressing CD4+CD25(high) regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. Journal of immunology (Baltimore, Md: 1950). 2004; 173(2):1444-1453.
102. Uso M, Jantus-Lewintre E, Bremnes RM, Calabuig S, Blasco A, Pastor E, Borreda I, Molina-Pinelo S, Paz-Ares L, Guijarro R, Martorell M, Forteza J, Camps C, et al. Analysis of the immune microenvironment in resected non-small cell lung cancer: the prognostic value of different T lymphocyte markers. Oncotarget. 2016; doi: 10.18632/oncotarget.10811.
103. Wang Y, Sun J, Zheng R, Shao Q, Gao W, Song B, Chen X and Qu X. Regulatory T cells are an important prognostic factor in breast cancer: a systematic review and metaanalysis. Neoplasma. 2016; 63(5).
104. Sia KC, Huynh H, Chung AY, Ooi LL, Lim KH, Hui KM and Lam PY. Preclinical evaluation of transcriptional targeting strategy for human hepatocellular carcinoma in an orthotopic xenograft mouse model. Molecular cancer therapeutics. 2013; 12(8):1651-1664.
105. Sha M, Mao G, Wang G, Chen Y, Wu X and Wang Z. DZNep inhibits the proliferation of colon cancer HCT116 cells by inducing senescence and apoptosis. Acta pharmaceutica Sinica B. 2015; 5(3):188-193.
106. Balasubramanian S, Adhikary G and Eckert RL. The Bmi-1 polycomb protein antagonizes the (-)-epigallocatechin-3-gallate-dependent suppression of skin cancer cell survival. Carcinogenesis. 2010; 31(3):496-503.
107. Lin YH, Lee CC, Chang FR, Chang WH, Wu YC and Chang JG. 16-hydroxycleroda-3, 13-dien-15, 16-olide regulates the expression of histone-modifying enzymes PRC2 complex and induces apoptosis in CML K562 cells. Life sciences. 2011; 89(23-24):886-895.
108. Bao B, Ali S, Banerjee S, Wang Z, Logna F, Azmi AS, Kong D, Ahmad A, Li Y, Padhye S and Sarkar FH. Curcumin analogue CDF inhibits pancreatic tumor growth by switching on suppressor microRNAs and attenuating EZH2 expression. Cancer research. 2012; 72(1):335-345.
109. Kim W, Bird GH, Neff T, Guo G, Kerenyi MA, Walensky LD and Orkin SH. Targeted disruption of the EZH2-EED complex inhibits EZH2-dependent cancer. Nature chemical biology. 2013; 9(10):643-650.
110. 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, et al. Astemizole arrests the proliferation of cancer cells by disrupting the EZH2-EED interaction of polycomb repressive complex 2. Journal of medicinal chemistry. 2014; 57(22):9512-9521.
111. 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, et al. Identification of Potent, Selective, Cell-Active Inhibitors of the Histone Lysine Methyltransferase EZH2. ACS medicinal chemistry letters. 2012; 3(12):1091-1096.
112. Wu C, Jin X, Yang J, Yang Y, He Y, Ding L, Pan Y, Chen S, Jiang J and Huang H. Inhibition of EZH2 by chemo-and radiotherapy agents and small molecule inhibitors induces cell death in castration-resistant prostate cancer. Oncotarget. 2016; 7(3):3440-3452.
113. Tiffen JC, Gunatilake D, Gallagher SJ, Gowrishankar K, Heinemann A, Cullinane C, Dutton-Regester K, Pupo GM, Strbenac D, Yang JY, Madore J, Mann GJ, Hayward NK, et al. Targeting activating mutations of EZH2 leads to potent cell growth inhibition in human melanoma by derepression of tumor suppressor genes. Oncotarget. 2015; 6(29):27023-27036.
114. Chen YT, Zhu F, Lin WR, Ying RB, Yang YP and Zeng LH. The novel EZH2 inhibitor, GSK126, suppresses cell migration and angiogenesis via down-regulating VEGF-A. Cancer chemotherapy and pharmacology. 2016; 77(4):757-765.
115. 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, et al. EPZ011989, A Potent, Orally-Available EZH2 Inhibitor with Robust in Vivo Activity. ACS medicinal chemistry letters. 2015; 6(5):491-495.
116. Song X, Gao T, Wang N, Feng Q, You X, Ye T, Lei Q, Zhu Y, Xiong M, Xia Y, Yang F, Shi Y, Wei Y, et al. Selective inhibition of EZH2 by ZLD1039 blocks H3K27methylation and leads to potent anti-tumor activity in breast cancer. Scientific reports. 2016; 6:20864.
117. 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, et al. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Molecular cancer therapeutics. 2014; 13(4):842-854.
118. Alimova I, Birks DK, Harris PS, Knipstein JA, Venkataraman S, Marquez VE, Foreman NK and Vibhakar R. Inhibition of EZH2 suppresses self-renewal and induces radiation sensitivity in atypical rhabdoid teratoid tumor cells. Neuro-oncology. 2013; 15(2):149-160.
119. Xia H, Yu CH, Zhang Y, Yu J, Li J, Zhang W, Zhang B, Li Y and Guo N. EZH2 silencing with RNAi enhances irradiation-induced inhibition of human lung cancer growth in vitro and in vivo. Oncology letters. 2012; 4(1):135-140.
120. Fillmore CM, Xu C, Desai PT, Berry JM, Rowbotham SP, Lin YJ, Zhang H, Marquez VE, Hammerman PS, Wong KK and Kim CF. EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumours to TopoII inhibitors. Nature. 2015; 520(7546):239-242.
121. Smonskey M, Lasorsa E, Rosario S, Kirk JS, Hernandez-Ilizaliturri FJ and Ellis L. EZH2 inhibition re-sensitizes multidrug resistant B-cell lymphomas to etoposide mediated apoptosis. Oncoscience. 2016; 3(1):21-30.
122. Kirk JS, Schaarschuch K, Dalimov Z, Lasorsa E, Ku S, Ramakrishnan S, Hu Q, Azabdaftari G, Wang J, Pili R and Ellis L. Top2a identifies and provides epigenetic rationale for novel combination therapeutic strategies for aggressive prostate cancer. Oncotarget. 2015; 6(5):3136-3146.
123. Neo WH, Lim JF, Grumont R, Gerondakis S and Su IH. c-Rel regulates Ezh2 expression in activated lymphocytes and malignant lymphoid cells. The Journal of biological chemistry. 2014; 289(46):31693-31707.
124. Su KJ, Lin CW, Chen MK, Yang SF and Yu YL. Effects of EZH2 promoter polymorphisms and methylation status on oral squamous cell carcinoma susceptibility and pathology. American journal of cancer research. 2015; 5(11):3475-3484.
125. Yu YL, Su KJ, Hsieh MJ, Wang SS, Wang PH, Weng WC and Yang SF. Impact of EZH2 polymorphisms on urothelial cell carcinoma susceptibility and clinicopathologic features. PloS one. 2014; 9(4):e93635.
126. Yu YL, Su KJ, Hsieh YH, Lee HL, Chen TY, Hsiao PC and Yang SF. Effects of EZH2 polymorphisms on susceptibility to and pathological development of hepatocellular carcinoma. PloS one. 2013; 8(9):e74870.
127. Wang J, Ma ZB, Li K and Guo GH. Association between EZH2 polymorphisms and colorectal cancer risk in Han Chinese population. Medical oncology (Northwood, London, England). 2014; 31(3):874.
128. Ma ZB, Guo GH, Niu Q and Shi N. Role of EZH2 polymorphisms in esophageal squamous cell carcinoma risk in Han Chinese population. International journal of molecular sciences. 2014; 15(7):12688-12697.
129. Zhou Y, Du WD, Wu Q, Liu Y, Chen G, Ruan J, Xu S, Yang F, Zhou FS, Tang XF, Tang HY, Zuo XB, Zhang FY, et al. EZH2 genetic variants affect risk of gastric cancer in the Chinese Han population. Molecular carcinogenesis. 2014; 53(8):589-597.
130. Paolicchi E, Pacetti P, Giovannetti E, Mambrini A, Orlandi M, Crea F, Romani AA, Tartarini R, Danesi R, Peters GJ and Cantore M. A single nucleotide polymorphism in EZH2 predicts overall survival rate in patients with cholangiocarcinoma. Oncology letters. 2013; 6(5):1487-1491.
131. Crea F, Fornaro L, Paolicchi E, Masi G, Frumento P, Loupakis F, Salvatore L, Cremolini C, Schirripa M, Graziano F, Ronzoni M, Ricci V, Farrar WL, et al. An EZH2 polymorphism is associated with clinical outcome in metastatic colorectal cancer patients. Annals of oncology. 2012; 23(5):1207-1213.
132. Gao SB, Sun SL, Zheng QL, Zhang L, Zhu Y, Jin GH and Xue LX. Genetic alteration and misexpression of Polycomb group genes in hepatocellular carcinoma. American journal of cancer research. 2015; 5(10):2969-2979.
133. Yoon KA, Gil HJ, Han J, Park J and Lee JS. Genetic polymorphisms in the polycomb group gene EZH2 and the risk of lung cancer. Journal of thoracic oncology. 2010; 5(1):10-16.