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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front Med    2013, Vol. 7 Issue (2) : 231-241     DOI: 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 Authors: Ng Irene Oi-Lin,Email:iolng@hkucc.hku.hk; Wong Chun-Ming,Email:jackwong@pathology.hku.hk   
Issue Date: 05 June 2013
URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-013-0253-7     OR     http://academic.hep.com.cn/fmd/EN/Y2013/V7/I2/231
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.
Type of histone PTMsModification siteTranscriptional role
Lysine acetylationH3 (9th, 14th,18th, 56th)H4 (5th, 8th, 13th, 16th)H2A, H2BActivation
Lysine methylationH3 (4th, 36th, 79th)H3 (9th, 27th), H4 (20th)ActivationRepression
Serine/threonine phosphorylationH3 (3rd, 10th, 28th)H2A, H2BActivation
Arginine methylationH3 (17th, 23rd), H4 (3rd)Activation
Lysine ubiquitylationH2A (119th)H2B (120th)RepressionActivation
Lysine sumoylationH2A (126th), H2B (6th/7th)Repression
Proline isomerizationH3 (30th-38th)Activation/repression
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
PcG proteinExpressionin HCCMolecular consequenceReferences
PRC2EZH2IncreasedSilenced multiple tumor suppressor miRNAs (e.g., miR-139-5p, miR-125b) to promote metastasis [41]
Repressed Wnt antagonists (e.g., AXIN2, NKD1, PRICKLE1) to promote proliferation [44]
Inhibition of EZH2 downregulated stathmin1 to restrain tumor growth [85]
SUZ12Increased? [41]
DecreasedInduced SUZ12/PcG targets (e.g., IGFII, DKK2, DLK1) reexpression during HBV-mediated transformation [55]
EEDIncreased? [41]
PRC1BMI1IncreasedCooperated with the activated Ras signaling to drive HCC tumorigenicity [63]
Maintained self-renewal property of liver tumor-initiating cells [65]
RING1A/1B??
CBX?Cbx7 knockout mice were prone to developing HCC [69]
YY1Increased?[72,73]
RYBPDecreased?[77]
Tab.2  Aberrant expressions of core polycomb group (PcG) proteins and their molecular consequence in HCC development
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