Histone deacetylase HDAC8 promotes insulin resistance and β-catenin activation in NAFLD-associated hepatocellular carcinoma

Yuan Tian, Vincent W.S. Wong, Grace L.H. Wong, Weiqin Yang, Hanyong Sun, Jiayun Shen, Joanna H.M. Tong, Minnie Y.Y. Go, Yue S. Cheung, Paul B.S. Lai, Mingyan Zhou, Gang XU, Tim H.M. Huang, Jun Yu, Ka F. To, Alfred S.L. Cheng*, Henry L.Y. Chan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

62 Citations (Scopus)

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 obesitypromoted 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.

Original languageEnglish
Pages (from-to)4803-4816
Number of pages14
JournalCancer Research
Volume75
Issue number22
DOIs
Publication statusPublished - 15 Nov 2015

Scopus Subject Areas

  • Oncology
  • Cancer Research

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