An IGFBP4-AKT-EZH2 epigenetic circuitry in HBV-associated hepatocellular carcinoma
Refereed conference paper presented and published in conference proceedings

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AbstractHepatocellular carcinoma (HCC) is the major subtype in liver cancer. Most HCC cases are related to hepatitis B virus (HBV) of which HBV X protein (HBx) is pro-tumorigenic. Enhancer of zeste homolog 2 (EZH2) can epigenetically silence gene transcription through histone H3 lysine 27 trimethylation (H3K27me3). Aberrant EZH2 over-expression has been documented in many solid tumors including HCC. However, the mechanistic effects of excess H3K27me3 in HBV-associated HCC remain unclear.

Herein we investigated the role of H3K27me3 in a HBx transgenic (TG) model, in which the EZH2-mediated H3K27me3 was up-regulated during hepatocarcinogenesis. Integrated ChIP-seq and RNA-seq analysis revealed 1027 and 1359 H3K27me3-occupied and repressed genes in HCCs relative to different controls. Among the 611 common targets, 20 were known tumor suppressor genes (TSGs) in the literature. qRT-PCR demonstrated significant down-regulation of 15 potential TSGs in murine tumors compared with controls, of which 9 were shown to be re-activated in human HCC cells upon GSK126 treatment. In a cohort of human specimens, the expression of 6 candidate genes was significantly down-regulated in HBV-associated tumors compared with non-tumor tissues. Among these, insulin-like growth factor binding protein-4 (IGFBP4), a crucial antagonist of both IGF and Wnt pathways, was found to induce the phosphorylation of AKT and EZH2 to abrogate the tri-methylation of H3K27, which further promoted IGFBP4 expression and formed a positive feedback circuit to reverse the H3K27me3-dependent gene silencing. Functionally, IGFBP4 was a potent TSG in HCC cells, effective in causing cell cycle arrest and inducing apoptosis, thereby suppressing cell growth and xenograft development. Of clinical significance, IGFBP4 ablation correlated with shorter overall and disease-free survival of HCC patients.

These findings show that HBx induces hepatocarcinogenesis through H3K27me3-mediated repression of TSGs, in which the IGFBP4-pAKT-pEZH2 signaling is a novel self-reinforcing circuit important for the regulation of epigenetic field in HCC.

Acknowledgements: This study is supported by the Collaborative Research Fund (C4017-14G) and the General Research Fund (14102914, 14120816) of the Research Grants Council, the National Natural Science Foundation of China (81272305, 81302167), and the Focused Investments Scheme B (1907309) of the Chinese University of Hong Kong.
Name of ConferenceThe 3rd Taiwan Epigenomics Symposium and International Conference on Systems Biology
Start Date of Conference17/03/2017
End Date of Conference18/03/2017
Place of ConferenceTaiwan
Country/Region of ConferenceTaiwan
LanguagesEnglish-United States

Last updated on 2018-15-05 at 12:36