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.