Targeting H3K27 trimethylation epigenome for liver cancer prevention: abridged secondary publication
ASL Cheng1,2, HT Wang3, DPF Tsang4, YY Lee4, W Kang5, KF To2,5
1 School of Biomedical Sciences, The Chinese University of Hong Kong
2 State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong
3 School of Public Health and Primary Care, The Chinese University of Hong Kong
4 Department of Medicine and Therapeutics, The Chinese University of Hong Kong
5 Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong
1. In hepatitis B virus (HBV) endemic areas such as Mainland China and Hong Kong, hepatocellular carcinoma (HCC) is a common manifestation of chronic HBV carriers. Cancer genome sequencing studies have demonstrated that epigenome disruption is a major hallmark of HCC.
2. The HBV X protein (HBx) has been shown to up-regulate the polycomb protein enhancer of zeste homolog 2 (EZH2), which catalyses tumour suppressor gene silencing via histone H3 lysine 27 trimethylation (H3K27me3). The identification of genomic repertoire of H3K27me3 targets and the polycomb recruiters for H3K27me3 deposition provide insights into molecular carcinogenesis and development of novel therapeutic strategies.
3. Using an integrated high-resolution genome-wide approach, we have characterised the HBx-deregulated H3K27me3 epigenome in HBx-transgenic HCC model. Our integrative study demonstrates that Ying yang 1 overexpression contributes to EZH2 recruitment for H3K27me3-mediated repression of tumour-suppressive protein–coding and microRNA genes, thereby enhancing nuclear factor-kappa B signalling in hepatocarcinogenesis.
4. Despite the survival improvement in HCC patients receiving multi-kinase-targeted inhibitor, the outcomes are still far from satisfactory. Given the availability of potent EZH2 inhibitors and their significant effects in reactivating tumour suppressor genes in HCC cells, further testing is warranted to determine if it is an effective chemopreventive strategy in patients with HBV-associated precancerous lesions. Targeting H3K27me3 epigenome for HCC prevention might benefit large populations of chronically HBV-infected patients.