Epigenetic dysregulation in hepatocellular carcinoma: focus on polycomb group proteins

doi:10.1007/s11684-013-0253-7

Front Med

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Issue () : 231-241 https://doi.org/10.1007/s11684-013-0253-7

REVIEW

Epigenetic dysregulation in hepatocellular carcinoma: focus on polycomb group proteins

Sandy Leung-Kuen Au, Irene Oi-Lin Ng(

), Chun-Ming Wong(

)

State Key Laboratory for Liver Research and Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

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Abstract

Hepatocellular carcinoma (HCC) development is characterized by the presence of epigenetic alterations, including promoter DNA hypermethylation and post-translational modifications of histone, which profoundly affect expression of a wide repertoire of genes critical for cancer development. Emerging data suggest that deregulation of polycomb group (PcG) proteins, which are key chromatin modifiers repressing gene transcription during developmental stage, plays a causative role in oncogenesis. PcG proteins assemble into polycomb repressive complex 1 (PRC1) and polycomb repressive complex 2 (PRC2) to impose the histone H3 lysine 27 trimethylation (H3K27me3) modification for repression. In this review, we will first recapitulate the mechanisms of two key epigenetic pathways: DNA methylation and histone modifications. Specifically, we will focus our discussion on the molecular roles of PcG proteins. Next, we will highlight recent findings on PcG proteins, their clinicopathological implication and their downstream molecular consequence in hepatocarcinogenesis. Last but not least, we will consider the therapeutic potential of targeting enhancer of zeste homolog 2 (EZH2) as a possible treatment for HCC. Improving our understanding on the roles of PcG proteins in hepatocarcinogenesis can benefit the development of epigenetic-based therapy.

Keywords liver cancer epigenetics histone modifications polycomb group proteins enhancer of zeste homolog 2 (EZH2)

Corresponding Author(s): Ng Irene Oi-Lin,Email:iolng@hkucc.hku.hk; Wong Chun-Ming,Email:jackwong@pathology.hku.hk

Issue Date: 05 June 2013

Cite this article:

Sandy Leung-Kuen Au,Irene Oi-Lin Ng,Chun-Ming Wong. Epigenetic dysregulation in hepatocellular carcinoma: focus on polycomb group proteins[J]. Front Med, 0, (): 231-241.

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https://academic.hep.com.cn/fmd/EN/10.1007/s11684-013-0253-7
https://academic.hep.com.cn/fmd/EN/Y0/V/I/231

Fig.1 Post-translational modification of histone amino (N)-terminal tails. The nucleosome contains an octamer of histone molecules (2 copies of histone H2A, H2B, H3 and H4) wrapped around by 147 bp of DNA strand. Histone N-terminal tails protruding from nucleosome core are subject to variety of post-translational modifications at the specific amino acid residues. Me: methylation; P: phosphorylation; Ac: acetylation; Ub: ubiquitylation.

Tab.1 Histone post-translational modifications (PTMs) convey specific transcriptional consequence

Fig.2 Polycomb group proteins assemble into two central complexes, the polycomb repressive complex 2 (PCR2) and polycomb repressive complex 1 (PRC1). In the PRC2, the core subunits include EZH2, EED and SUZ12. In the PRC1, the core subunits include RING1A/1B, BMI1 and CBX. Other substoichiometric subunits are also shown.

Fig.3 PcG-mediated epigenetic silencing. In the canonical model, PRC2 is recruited to target gene loci and EZH2 catalyzes trimethylation on histone H3 lysine 27 (H3K27me3). Subsequently, PRC1 is recruited to the site, of which the chromodomain of CBX proteins can recognize and bind to the H3K27me3 mark. RING1A/1B can further monoubiquitylate histone H2A lysine 119 (H2AK119ub1). Altogether, a repressive chromatin environment is established to inhibit transcription

Tab.2 Aberrant expressions of core polycomb group (PcG) proteins and their molecular consequence in HCC development

1	Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61(2): 69–90 doi: 10.3322/caac.20107 pmid:21296855
2	Ferlay Ja. GLOBOCAN 2008, Cancer Incidence and Mortality Worldwide: IARC CancerBase. 2008; Available from: http://globocan.iarc.fr/(Accessed on October 1, 2012)
3	Tang ZY. Hepatocellular carcinoma—cause, treatment and metastasis. World J Gastroenterol 2001; 7(4): 445–454 pmid:11819809
4	Jones PA, Baylin SB. The epigenomics of cancer. Cell 2007; 128(4): 683–692 doi: 10.1016/j.cell.2007.01.029 pmid:17320506
5	Jones PA, Laird PW. Cancer epigenetics comes of age. Nat Genet 1999; 21(2): 163–167 doi: 10.1038/5947 pmid:9988266
6	Riggs AD. X inactivation, differentiation, and DNA methylation. Cytogenet Cell Genet 1975; 14(1): 9–25 doi: 10.1159/000130315 pmid:1093816
7	Holliday R, Pugh JE. DNA modification mechanisms and gene activity during development. Science 1975; 187(4173): 226–232 doi: 1111098" target="_blank">10.1126/science. pmid:1111098 pmid:1111098
8	Kondoh N, Wakatsuki T, Hada A, Shuda M, Tanaka K, Arai M, Yamamoto M. Genetic and epigenetic events in human hepatocarcinogenesis. Int J Oncol 2001; 18(6): 1271–1278 pmid:11351262
9	Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002; 3(6): 415–428 pmid:12042769
10	Turker MS. The establishment and maintenance of DNA methylation patterns in mouse somatic cells. Semin Cancer Biol 1999; 9(5): 329–337 doi: 10.1006/scbi.1999.0133 pmid:10547341
11	Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N, Strouboulis J, Wolffe AP. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet 1998; 19(2): 187–191 doi: 10.1038/561 pmid:9620779
12	Wong CM, Ng YL, Lee JM, Wong CC, Cheung OF, Chan CY, Tung EK, Ching YP, Ng IO. Tissue factor pathway inhibitor-2 as a frequently silenced tumor suppressor gene in hepatocellular carcinoma. Hepatology 2007; 45(5): 1129–1138 doi: 10.1002/hep.21578 pmid:17464989
13	Tung EK, Wong CM, Yau TO, Lee JM, Ching YP, Ng IO. HAI-2 is epigenetically downregulated in human hepatocellular carcinoma, and its Kunitz domain type 1 is critical for anti-invasive functions. Int J Cancer 2009; 124(8): 1811–1819 doi: 10.1002/ijc.24115 pmid:19107935
14	Gama-Sosa MA, Slagel VA, Trewyn RW, Oxenhandler R, Kuo KC, Gehrke CW, Ehrlich M. The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res 1983; 11(19): 6883–6894 doi: 10.1093/nar/11.19.6883 pmid:6314264
15	Lister R, Ecker JR. Finding the fifth base: genome-wide sequencing of cytosine methylation. Genome Res 2009; 19(6): 959–966 doi: 10.1101/gr.083451.108 pmid:19273618
16	Kanai Y. Genome-wide DNA methylation profiles in precancerous conditions and cancers. Cancer Sci 2010; 101(1): 36–45 doi: 10.1111/j.1349-7006.2009.01383.x pmid:19891661
17	Ehrlich M. DNA methylation in cancer: too much, but also too little. Oncogene 2002; 21(35): 5400–5413 doi: 10.1038/sj.onc.1205651 pmid:12154403
18	Saito Y, Kanai Y, Sakamoto M, Saito H, Ishii H, Hirohashi S. Expression of mRNA for DNA methyltransferases and methyl-CpG-binding proteins and DNA methylation status on CpG islands and pericentromeric satellite regions during human hepatocarcinogenesis. Hepatology 2001; 33(3): 561–568 doi: 10.1053/jhep.2001.22507 pmid:11230735
19	Kornberg RD, Lorch Y. Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell 1999; 98(3): 285–294 doi: 10.1016/S0092-8674(00)81958-3 pmid:10458604
20	B?hm L, Crane-Robinson C. Proteases as structural probes for chromatin: the domain structure of histones. Biosci Rep 1984; 4(5): 365–386 doi: 10.1007/BF01122502 pmid:6375755
21	Strahl BD, Allis CD. The language of covalent histone modifications. Nature 2000; 403(6765): 41–45 doi: 10.1038/47412 pmid:10638745
22	Jenuwein T, Allis CD. Translating the histone code. Science 2001; 293(5532): 1074–1080 doi: 10.1126/science.1063127 pmid:11498575
23	Lewis EB. A gene complex controlling segmentation in Drosophila. Nature 1978; 276(5688): 565–570 doi: 10.1038/276565a0 pmid:103000
24	Levine SS, King IF, Kingston RE. Division of labor in polycomb group repression. Trends Biochem Sci 2004; 29(9): 478–485 doi: 10.1016/j.tibs.2004.07.007 pmid:15337121
25	Otte AP, Kwaks TH. Gene repression by Polycomb group protein complexes: a distinct complex for every occasion? Curr Opin Genet Dev 2003; 13(5): 448–454 doi: 10.1016/S0959-437X(03)00108-4 pmid:14550408
26	Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones RS, Zhang Y. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 2002; 298(5595): 1039–1043 doi: 10.1126/science.1076997 pmid:12351676
27	Sing A, Pannell D, Karaiskakis A, Sturgeon K, Djabali M, Ellis J, Lipshitz HD, Cordes SP. A vertebrate Polycomb response element governs segmentation of the posterior hindbrain. Cell 2009; 138(5): 885–897 doi: 10.1016/j.cell.2009.08.020 pmid:19737517
28	Plath K, Fang J, Mlynarczyk-Evans SK, Cao R, Worringer KA, Wang H, de la Cruz CC, Otte AP, Panning B, Zhang Y. Role of histone H3 lysine 27 methylation in X inactivation. Science 2003; 300(5616): 131–135 doi: 10.1126/science.1084274 pmid:12649488
29	Pandey RR, Mondal T, Mohammad F, Enroth S, Redrup L, Komorowski J, Nagano T, Mancini-Dinardo D, Kanduri C. Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation. Mol Cell 2008; 32(2): 232–246 doi: 10.1016/j.molcel.2008.08.022 pmid:18951091
30	Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, Goodnough LH, Helms JA, Farnham PJ, Segal E, Chang HY. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 2007; 129(7): 1311–1323 doi: 10.1016/j.cell.2007.05.022 pmid:17604720
31	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, Murray HL, Zucker JP, Yuan B, Bell GW, Herbolsheimer E, Hannett NM, Sun K, Odom DT, Otte AP, Volkert TL, Bartel DP, Melton DA, Gifford DK, Jaenisch R, Young RA. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 2006; 125(2): 301–313 doi: 10.1016/j.cell.2006.02.043 pmid:16630818
32	Bracken AP, Dietrich N, Pasini D, Hansen KH, Helin K. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev 2006; 20(9): 1123–1136 doi: 10.1101/gad.381706 pmid:16618801
33	Boyer LA, Plath K, Zeitlinger J, Brambrink T, Medeiros LA, Lee TI, Levine SS, Wernig M, Tajonar A, Ray MK, Bell GW, Otte AP, Vidal M, Gifford DK, Young RA, Jaenisch R. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 2006; 441(7091): 349–353 doi: 10.1038/nature04733 pmid:16625203
34	Juan AH, Kumar RM, Marx JG, Young RA, Sartorelli V. Mir-214-dependent regulation of the polycomb protein Ezh2 in skeletal muscle and embryonic stem cells. Mol Cell 2009; 36(1): 61–74 doi: 10.1016/j.molcel.2009.08.008 pmid:19818710
35	Montgomery ND, Yee D, Chen A, Kalantry S, Chamberlain SJ, Otte AP, Magnuson T. The murine polycomb group protein Eed is required for global histone H3 lysine-27 methylation. Curr Biol 2005 24;15(10): 942–947 15916951 doi: 10.1016/j.cub.2005.04.051
36	Pasini D, Bracken AP, Jensen MR, Lazzerini Denchi E, Helin K. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J 2004; 23(20): 4061–4071 doi: 10.1038/sj.emboj.7600402 pmid:15385962
37	Cao R, Zhang Y. SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. Mol Cell 2004; 15(1): 57–67 doi: 10.1016/j.molcel.2004.06.020 pmid:15225548
38	Cai MY, Tong ZT, Zheng F, Liao YJ, Wang Y, Rao HL, Chen YC, Wu QL, Liu YH, Guan XY, Lin MC, Zeng YX, Kung HF, Xie D. EZH2 protein: a promising immunomarker for the detection of hepatocellular carcinomas in liver needle biopsies. Gut 2011; 60(7): 967–976 doi: 10.1136/gut.2010.231993 pmid:21330577
39	Sasaki M, Ikeda H, Itatsu K, Yamaguchi J, Sawada S, Minato H, Ohta T, Nakanuma Y. The overexpression of polycomb group proteins Bmi1 and EZH2 is associated with the progression and aggressive biological behavior of hepatocellular carcinoma. Lab Invest 2008; 88(8): 873–882 doi: 10.1038/labinvest.2008.52 pmid:18591938
40	Sudo T, Utsunomiya T, Mimori K, Nagahara H, Ogawa K, Inoue H, Wakiyama S, Fujita H, Shirouzu K, Mori M. Clinicopathological significance of EZH2 mRNA expression in patients with hepatocellular carcinoma. Br J Cancer 2005; 92(9): 1754–1758 doi: 10.1038/sj.bjc.6602531 pmid:15856046
41	Au SL, Wong CC, Lee JM, Fan DN, Tsang FH, Ng IO, Wong CM. Enhancer of zeste homolog 2 epigenetically silences multiple tumor suppressor microRNAs to promote liver cancer metastasis. Hepatology 2012; 56(2): 622–631 doi: 10.1002/hep.25679 pmid:22370893
42	Cai MY, Hou JH, Rao HL, Luo RZ, Li M, Pei XQ, Lin MC, Guan XY, Kung HF, Zeng YX, Xie D. High expression of H3K27me3 in human hepatocellular carcinomas correlates closely with vascular invasion and predicts worse prognosis in patients. Mol Med 2011; 17(1–2): 12–20 doi: 10.2119/molmed.2010.00103 pmid:20844838
43	Takigawa Y, Brown AM. Wnt signaling in liver cancer. Curr Drug Targets 2008; 9(11): 1013–1024 doi: 10.2174/138945008786786127 pmid:18991612
44	Cheng AS, Lau SS, Chen Y, Kondo Y, Li MS, Feng H, Ching AK, Cheung KF, Wong HK, Tong JH, Jin H, Choy KW, Yu J, To KF, Wong N, Huang TH, Sung JJ. EZH2-mediated concordant repression of Wnt antagonists promotes β-catenin-dependent hepatocarcinogenesis. Cancer Res 2011; 71(11): 4028–4039 doi: 10.1158/0008-5472.CAN-10-3342 pmid:21512140
45	Gramantieri L, Fornari F, Callegari E, Sabbioni S, Lanza G, Croce CM, Bolondi L, Negrini M. MicroRNA involvement in hepatocellular carcinoma. J Cell Mol Med 2008; 12(6A): 2189–2204 doi: 10.1111/j.1582-4934.2008.00533.x pmid:19120703
46	Ji J, Wang XW. New kids on the block: diagnostic and prognostic microRNAs in hepatocellular carcinoma. Cancer Biol Ther 2009; 8(18): 1686–1693 pmid:19901517
47	Huntzinger E, Izaurralde E. Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet 2011; 12(2): 99–110 doi: 10.1038/nrg2936 pmid:21245828
48	Zheng F, Liao YJ, Cai MY, Liu YH, Liu TH, Chen SP, Bian XW, Guan XY, Lin MC, Zeng YX, Kung HF, Xie D. The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2. Gut 2012; 61(2): 278–289 doi: 10.1136/gut.2011.239145 pmid:21672940
49	Varambally S, Cao Q, Mani RS, Shankar S, Wang X, Ateeq B, Laxman B, Cao X, Jing X, Ramnarayanan K, Brenner JC, Yu J, Kim JH, Han B, Tan P, Kumar-Sinha C, Lonigro RJ, Palanisamy N, Maher CA, Chinnaiyan AM. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science 2008; 322(5908): 1695–1699 doi: 10.1126/science.1165395 pmid:19008416
50	Sander S, Bullinger L, Klapproth K, Fiedler K, Kestler HA, Barth TF, M?ller P, Stilgenbauer S, Pollack JR, Wirth T. MYC stimulates EZH2 expression by repression of its negative regulator miR-26a. Blood 2008; 112(10): 4202–4212 doi: 10.1182/blood-2008-03-147645 pmid:18713946
51	Cao Q, Mani RS, Ateeq B, Dhanasekaran SM, Asangani IA, Prensner JR, Kim JH, Brenner JC, Jing X, Cao X, Wang R, Li Y, Dahiya A, Wang L, Pandhi M, Lonigro RJ, Wu YM, Tomlins SA, Palanisamy N, Qin Z, Yu J, Maher CA, Varambally S, Chinnaiyan AM. Coordinated regulation of polycomb group complexes through microRNAs in cancer. Cancer Cell 2011; 20(2): 187–199 doi: 10.1016/j.ccr.2011.06.016 pmid:21840484
52	Squazzo SL, O’Geen H, Komashko VM, Krig SR, Jin VX, Jang SW, Margueron R, Reinberg D, Green R, Farnham PJ. Suz12 binds to silenced regions of the genome in a cell-type-specific manner. Genome Res 2006; 16(7): 890–900 doi: 10.1101/gr.5306606 pmid:16751344
53	Kirmizis A, Bartley SM, Farnham PJ. Identification of the polycomb group protein SU(Z)12 as a potential molecular target for human cancer therapy. Mol Cancer Ther 2003; 2(1): 113–121 pmid:12533679
54	Wang WH, Studach LL, Andrisani OM. Proteins ZNF198 and SUZ12 are down-regulated in hepatitis B virus (HBV) X protein-mediated hepatocyte transformation and in HBV replication. Hepatology 2011; 53(4): 1137–1147 doi: 10.1002/hep.24163 pmid:21480320
55	Studach LL, Menne S, Cairo S, Buendia MA, Hullinger RL, Lefran?ois L, Merle P, Andrisani OM. A subset of Suz12/PRC2 target genes is activated during HBV replication and liver carcinogenesis associated with hepatitis B virus X protein.Hepatology 2012; 56(4): 1240–1251 doi: 10.1002/hep.25781 pmid:22505317
56	Gao Z, Zhang J, Bonasio R, Strino F, Sawai A, Parisi F, Kluger Y, Reinberg D. PCGF homologs, CBX proteins, and RYBP define functionally distinct PRC1 family complexes. Mol Cell 2012; 45(3): 344–356 doi: 10.1016/j.molcel.2012.01.002 pmid:22325352
57	Morey L, Pascual G, Cozzuto L, Roma G, Wutz A, Benitah SA, Di Croce L. Nonoverlapping functions of the Polycomb group Cbx family of proteins in embryonic stem cells. Cell Stem Cell 2012; 10(1): 47–62 doi: 10.1016/j.stem.2011.12.006 pmid:22226355
58	van der Lugt NM, Alkema M, Berns A, Deschamps J. The Polycomb-group homolog Bmi-1 is a regulator of murine Hox gene expression. Mech Dev 1996; 58(1–2): 153–164 doi: 10.1016/S0925-4773(96)00570-9 pmid:8887324
59	Akasaka T, Kanno M, Balling R, Mieza MA, Taniguchi M, Koseki H. A role for mel-18, a polycomb group-related vertebrate gene, during theanteroposterior specification of the axial skeleton. Development 1996; 122(5): 1513–1522 pmid:8625838
60	Effendi K, Mori T, Komuta M, Masugi Y, Du W, Sakamoto M. Bmi-1 gene is upregulated in early-stage hepatocellular carcinoma and correlates with ATP-binding cassette transporter B1 expression. Cancer Sci 2010; 101(3): 666–672 doi: 10.1111/j.1349-7006.2009.01431.x pmid:20085590
61	Wang H, Pan K, Zhang HK, Weng DS, Zhou J, Li JJ, Huang W, Song HF, Chen MS, Xia JC. Increased polycomb-group oncogene Bmi-1 expression correlates with poor prognosis in hepatocellular carcinoma. J Cancer Res Clin Oncol 2008; 134(5): 535–541 doi: 10.1007/s00432-007-0316-8 pmid:17917742
62	Schuringa JJ, Vellenga E. Role of the polycomb group gene BMI1 in normal and leukemic hematopoietic stem and progenitor cells. Curr Opin Hematol 2010; 17(4): 294–299 doi: 10.1097/MOH.0b013e328338c439 pmid:20308890
63	Xu CR, Lee S, Ho C, Bommi P, Huang SA, Cheung ST, Dimri GP, Chen X. Bmi1 functions as an oncogene independent of Ink4A/Arf repression in hepatic carcinogenesis. Mol Cancer Res 2009; 7(12): 1937–1945 doi: 10.1158/1541-7786.MCR-09-0333 pmid:19934271
64	Chiba T, Zheng YW, Kita K, Yokosuka O, Saisho H, Onodera M, Miyoshi H, Nakano M, Zen Y, Nakanuma Y, Nakauchi H, Iwama A, Taniguchi H. Enhanced self-renewal capability in hepatic stem/progenitor cells drives cancer initiation. Gastroenterology 2007; 133(3): 937–950 doi: 10.1053/j.gastro.2007.06.016 pmid:17673212
65	Chiba T, Miyagi S, Saraya A, Aoki R, Seki A, Morita Y, Yonemitsu Y, Yokosuka O, Taniguchi H, Nakauchi H, Iwama A. The polycomb gene product BMI1 contributes to the maintenance of tumor-initiating side population cells in hepatocellular carcinoma. Cancer Res 2008; 68(19): 7742–7749 doi: 10.1158/0008-5472.CAN-07-5882 pmid:18829528
66	O’Loghlen A, Mu?oz-Cabello AM, Gaspar-Maia A, Wu HA, Banito A, Kunowska N, Racek T, Pemberton HN, Beolchi P, Lavial F, Masui O, Vermeulen M, Carroll T, Graumann J, Heard E, Dillon N, Azuara V, Snijders AP, Peters G, Bernstein E, Gil J. MicroRNA regulation of Cbx7 mediates a switch of Polycomb orthologs during ESC differentiation. Cell Stem Cell 2012; 10(1): 33–46 doi: 10.1016/j.stem.2011.12.004 pmid:22226354
67	Karamitopoulou E, Pallante P, Zlobec I, Tornillo L, Carafa V, Schaffner T, Borner M, Diamantis I, Esposito F, Brunner T, Zimmermann A, Federico A, Terracciano L, Fusco A. Loss of the CBX7 protein expression correlates with a more aggressive phenotype in pancreatic cancer. Eur J Cancer 2010; 46(8): 1438–1444 doi: 10.1016/j.ejca.2010.01.033 pmid:20185297
68	Pallante P, Terracciano L, Carafa V, Schneider S, Zlobec I, Lugli A, Bianco M, Ferraro A, Sacchetti S, Troncone G, Fusco A, Tornillo L. The loss of the CBX7 gene expression represents an adverse prognostic marker for survival of colon carcinoma patients. Eur J Cancer 2010; 46(12): 2304–2313 doi: 10.1016/j.ejca.2010.05.011 pmid:20542683
69	Forzati F, Federico A, Pallante P, Abbate A, Esposito F, Malapelle U, Sepe R, Palma G, Troncone G, Scarfò M, Arra C, Fedele M, Fusco A. CBX7 is a tumor suppressor in mice and humans. J Clin Invest 2012; 122(2): 612–623 doi: 10.1172/JCI58620 pmid:22214847
70	Brown JL, Mucci D, Whiteley M, Dirksen ML, Kassis JA. The Drosophila Polycomb group gene pleiohomeotic encodes a DNA binding protein with homology to the transcription factor YY1. Mol Cell 1998; 1(7): 1057–1064 doi: 10.1016/S1097-2765(00)80106-9 pmid:9651589
71	Wilkinson FH, Park K, Atchison ML. Polycomb recruitment to DNA in vivo by the YY1 REPO domain. Proc Natl Acad Sci USA 2006; 103(51): 19296–19301 doi: 10.1073/pnas.0603564103 pmid:17158804
72	Notarbartolo M, Giannitrapani L, Vivona N, Poma P, Labbozzetta M, Florena A M, Porcasi R, Rosario Muggeo V M, Sandonato L, Cervello M, Montalto G, D’Alessandro N. Frequent alteration of the Yin Yang 1/Raf-1 kinase inhibitory protein ratio in hepatocellular carcinoma. OMICS: A Journal of Integrative Biology2011; 15(5): 267–272 doi: 10.1089/omi.2010.0096
73	Zhang S, Jiang T, Feng L, Sun J, Lu H, Wang Q, Pan M, Huang D, Wang X, Wang L, Jin H. Yin Yang-1 suppresses differentiation of hepatocellular carcinoma cells through the downregulation of CCAAT/enhancer-binding protein alpha. J Mol Med (Berl) 2012; 90(9): 1069–1077 doi: 10.1007/s00109-012-0879-y pmid:22391813
74	Zhang L, Cai X, Chen K, Wang Z, Wang L, Ren M, Huang A, Tang H. Hepatitis B virus protein up-regulated HLJ1 expression via the transcription factor YY1 in human hepatocarcinoma cells. Virus Res 2011; 157(1): 76–81 doi: 10.1016/j.virusres.2011.02.009 pmid:21345358
75	García E, Marcos-Gutiérrez C, del Mar Lorente M, Moreno JC, Vidal M. RYBP, a new repressor protein that interacts with components of the mammalian polycomb complex, and with the transcription factor YY1. EMBO J 1999; 18(12): 3404–3418 doi: 10.1093/emboj/18.12.3404 pmid:10369680
76	Tavares L, Dimitrova E, Oxley D, Webster J, Poot R, Demmers J, Bezstarosti K, Taylor S, Ura H, Koide H, Wutz A, Vidal M, Elderkin S, Brockdorff N. RYBP-PRC1 complexes mediate H2A ubiquitylation at polycomb target sites independently of PRC2 and H3K27me3. Cell 2012; 148(4): 664–678 doi: 10.1016/j.cell.2011.12.029 pmid:22325148
77	Chen D, Zhang J, Li M, Rayburn ER, Wang H, Zhang R. RYBP stabilizes p53 by modulating MDM2. EMBO Rep 2009; 10(2): 166–172 doi: 10.1038/embor.2008.231 pmid:19098711
78	Baylin SB, Jones PA. A decade of exploring the cancer epigenome- biological and translational implications. Nat Rev Cancer 2011; 11(10): 726–734 doi: 10.1038/nrc3130 pmid:21941284
79	Chiang PK, Cantoni GL. Perturbation of biochemical transmethylations by 3-deazaadenosine in vivo. Biochem Pharmacol 1979; 28(12): 1897–1902 doi: 10.1016/0006-2952(79)90642-7 pmid:454462
80	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(9): 1050–1063 doi: 10.1101/gad.1524107 pmid:17437993
81	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(6): 1579–1588 doi: 10.1158/1535-7163.MCT-09-0013 pmid:19509260
82	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(13): 2733–2743 doi: 10.1182/blood-2009-03-213496 pmid:19638619
83	Cheng LL, Itahana Y, Lei ZD, Chia NY, Wu Y, Yu Y, Zhang SL, Thike AA, Pandey A, Rozen S, Voorhoeve PM, Yu Q, Tan PH, Bay BH, Itahana K, Tan P. TP53 genomic status regulates sensitivity of gastric cancer cells to the histone methylation inhibitor 3-deazaneplanocin A (DZNep). Clin Cancer Res 2012 1;18(15): 4201–4212 doi: 10.1158/1078-0432.CCR-12-0036 pmid:22675170
84	Chiba T, Suzuki E, Negishi M, Saraya A, Miyagi S, Konuma T, Tanaka S, Tada M, Kanai F, Imazeki F, Iwama A, Yokosuka O. 3-Deazaneplanocin A is a promising therapeutic agent for the eradication of tumor-initiating hepatocellular carcinoma cells. Int J Cancer 2012; 130(11): 2557–2567 doi: 10.1002/ijc.26264 pmid:21717453
85	Chen Y, Lin MC, Yao H, Wang H, Zhang AQ, Yu J, Hui CK, Lau GK, He ML, Sung J, Kung HF. Lentivirus-mediated RNA interference targeting enhancer of zeste homolog 2 inhibits hepatocellular carcinoma growth through down-regulation of stathmin. Hepatology 2007; 46(1): 200–208 doi: 10.1002/hep.21668 pmid:17596871

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