title: Epigenetic regulation of hepatocellular carcinoma in non-alcoholic fatty liver disease.
abstract: Emerging evidence that epigenetics converts alterations in nutrient and metabolism into heritable pattern of gene expression has profound implications in understanding human physiology and diseases. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome including obesity and diabetes which elevate the risk of hepatocellular carcinoma (HCC) especially in male. This review focuses on the molecular connections between metabolic dysfunction and aberrant epigenetic alterations in the development of HCC in NAFLD. The metabolites derived from excessive insulin, glucose and lipid may perturb epigenetic gene regulation through DNA methylation, histone modifications, and RNA interference, leading to activation of pro-inflammatory signaling and deregulation of metabolic pathways. The interplay and crosstalk of chromatin-modifying enzymes, microRNAs, signaling pathways and the downstream transcription factors result in epigenomic reprogramming that drives hepatocellular transformation. The interactions between sex hormone pathways and the epigenetic machineries that influence chromatin states in NAFLD provide potential molecular mechanisms of gender disparity in HCC. A deeper understanding of these connections and comprehensive molecular catalog of hepatocarcinogenesis may shed light in the identification of druggable epigenetic targets for the prevention and treatment of HCC in obese or diabetic patients.
authors.affiliation: Institute of Digestive Disease and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tian
authors.forename: Vincent Wai-Sun
authors.initials: VW
authors.lastname: Wong
authors.forename: Henry Lik-Yuen
authors.initials: HL
authors.lastname: Chan
authors.forename: Alfred Sze-Lok
authors.initials: AS
authors.lastname: Cheng
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000209:etiology*; D044127:Epigenesis, Genetic; D005234:Fatty Liver / Q000150:complications* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000453:epidemiology / Q000209:etiology*; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease; D012737:Sex Factors; D015398:Signal Transduction
keywords: Chromatin modifications; Epigenetics; Hepatocellular carcinoma; Insulin resistance; Non-alcoholic steatohepatitis