title: Histone Deacetylase HDAC8 Promotes Insulin Resistance and β-Catenin Activation in NAFLD-Associated Hepatocellular Carcinoma.
abstract: The growing epidemic of obesity, which causes nonalcoholic fatty liver disease (NAFLD) and the more severe phenotype nonalcoholic steatohepatitis (NASH), has paralleled the increasing incidence of hepatocellular carcinoma (HCC). Accumulating evidence demonstrates that overnutrition and metabolic pathways can trigger modifications of DNA and histones via deregulation of chromatin modifiers, resulting in aberrant transcriptional activity. However, the epigenetic regulation of HCC development in NAFLD remains obscure. Here, we uncover key epigenetic regulators using both dietary and genetic obesity-promoted HCC models through quantitative expression profiling and characterize the oncogenic activities of histone deacetylase HDAC8 in NAFLD-associated hepatocarcinogenesis. HDAC8 is directly upregulated by the lipogenic transcription factor SREBP-1 where they are coexpressed in dietary obesity models of NASH and HCC. Lentiviral-mediated HDAC8 attenuation in vivo reversed insulin resistance and reduced NAFLD-associated tumorigenicity. HDAC8 modulation by genetic and pharmacologic approaches inhibited p53/p21-mediated apoptosis and G2-M phase cell-cycle arrest and stimulated β-catenin-dependent cell proliferation. Mechanistically, HDAC8 physically interacted with the chromatin modifier EZH2 to concordantly repress Wnt antagonists via histone H4 deacetylation and H3 lysine 27 trimethylation. In human NAFLD-associated HCC, levels of SREBP-1, HDAC8, EZH2, H4 deacetylation, H3K27me3, and active β-catenin were all correlated positively in tumors compared with nontumor tissues. Overall, our findings show how HDAC8 drives NAFLD-associated hepatocarcinogenesis, offering a novel epigenetic target to prevent or treat HCC in obese patients.
authors.affiliation: Department of Medicine and Therapeutics and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China. State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Medicine and Therapeutics and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China. State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Vincent W S
authors.initials: VW
authors.lastname: Wong
authors.affiliation: Department of Medicine and Therapeutics and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China. State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Grace L H
authors.initials: GL
authors.lastname: Wong
authors.affiliation: Department of Medicine and Therapeutics and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China. State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Weiqin
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Medicine and Therapeutics and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China. State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Hanyong
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Medicine and Therapeutics and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China. State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Jiayun
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Joanna H M
authors.initials: JH
authors.lastname: Tong
authors.affiliation: Department of Medicine and Therapeutics and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Minnie Y Y
authors.initials: MY
authors.lastname: Go
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Yue S
authors.initials: YS
authors.lastname: Cheung
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Paul B S
authors.initials: PB
authors.lastname: Lai
authors.affiliation: Department of Medicine and Therapeutics and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Mingyan
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Medicine and Therapeutics and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
authors.affiliation: Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Tim H M
authors.initials: TH
authors.lastname: Huang
authors.affiliation: Department of Medicine and Therapeutics and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China. State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Ka F
authors.initials: KF
authors.lastname: To
authors.affiliation: State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China. School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, PR China. alfredcheng@cuhk.edu.hk hlychan@cuhk.edu.hk.
authors.forename: Alfred S L
authors.initials: AS
authors.lastname: Cheng
authors.affiliation: Department of Medicine and Therapeutics and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China. State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China. alfredcheng@cuhk.edu.hk hlychan@cuhk.edu.hk.
authors.forename: Henry L Y
authors.initials: HL
authors.lastname: Chan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D063646:Carcinogenesis / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000209:etiology; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006655:Histone Deacetylases / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D007333:Insulin Resistance / Q000502:physiology; D008113:Liver Neoplasms / Q000201:enzymology* / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications*; D009765:Obesity / Q000150:complications*; D012097:Repressor Proteins / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism
chemical_list: D012097:Repressor Proteins; D051176:beta Catenin; C409470:HDAC8 protein, human; C000603105:HDAC8 protein, mouse; D006655:Histone Deacetylases