title: Epigenetic Activation of Wnt/β-Catenin Signaling in NAFLD-Associated Hepatocarcinogenesis.
abstract: Non-alcoholic fatty liver disease (NAFLD), characterized by fat accumulation in liver, is closely associated with central obesity, over-nutrition and other features of metabolic syndrome, which elevate the risk of developing hepatocellular carcinoma (HCC). The Wnt/β-catenin signaling pathway plays a significant role in the physiology and pathology of liver. Up to half of HCC patients have activation of Wnt/β-catenin signaling. However, the mutation frequencies of CTNNB1 (encoding β-catenin protein) or other antagonists targeting Wnt/β-catenin signaling are low in HCC patients, suggesting that genetic mutations are not the major factor driving abnormal β-catenin activities in HCC. Emerging evidence has demonstrated that obesity-induced metabolic pathways can deregulate chromatin modifiers such as histone deacetylase 8 to trigger undesired global epigenetic changes, thereby modifying gene expression program which contributes to oncogenic signaling. This review focuses on the aberrant epigenetic activation of Wnt/β-catenin in the development of NAFLD-associated HCC. A deeper understanding of the molecular mechanisms underlying such deregulation may shed light on the identification of novel druggable epigenetic targets for the prevention and/or treatment of HCC in obese and diabetic patients.
authors.affiliation: Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. teresaty1987@163.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tian
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China. mythmok@mythmok.com.|Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518057, China. mythmok@mythmok.com.
authors.forename: Myth T S
authors.initials: MT
authors.lastname: Mok
authors.affiliation: Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. pyyang@ibp.ac.cn.
authors.forename: Pengyuan
authors.initials: P
authors.lastname: Yang
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China. alfredcheng@cuhk.edu.hk.|Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518057, China. alfredcheng@cuhk.edu.hk.|State Key Laboratory of Digestive Disease and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China. alfredcheng@cuhk.edu.hk.
authors.forename: Alfred S L
authors.initials: AS
authors.lastname: Cheng
keywords: DNA methylation; HDAC8; Wnt; epigenetics; hepatocellular carcinoma; histone modification; microRNA; non-alcoholic fatty liver disease; β-catenin