Silencing of tumor suppressor IGFBP4 constitutes EZH2-driven epigenetic reprogramming in hepatocarcinogenesis
Refereed conference paper presented and published in conference proceedings

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AbstractAberrant H3K27 trimethylation mediated by EZH2 is a hallmark in hepatocellular carcinoma (HCC), but the underlying mechanistic effects remain incompletely understood. Using ChIPseq and RNA-seq, we identified the genomic loci silenced by Ezh2/H3K27me3 in HBxtransgenic mouse-derived HCCs, including Igfbp4 whose ablation significantly correlated with poor survival of HCC patients. Subsequent functional assays revealed the strong growth- and invasion-suppressive effects of IGFBP4, which was associated with transcriptomic alterations
leading to deregulation of multiple signaling pathways. Mechanistically, IGFBP4 promoted AKT/EZH2 phosphorylation to attenuate H3K27me3-mediated silencing, forming a reciprocal feedback loop that directed a transcription factor network crucial for liver homeostasis. Of translational significance, the in vivo tumorigenicity of IGFBP4-silenced HCC cells was effectively suppressed by pharmacological inhibition of EZH2, but not AKT. These collective data uncover IGFBP4 as a novel hepatic tumor suppressor, and shed light into the mechanistic basis of EZH2-targeted drugs for HCC treatment.
All Author(s) ListMyth T.S. MOK, Ying-Ying LEE, Wei KANG, Weiqin YANG, Wenshu TANG, Feng WU, Liangliang XU, Zhuo YU, Sau-Dan LEE, Grace L.H. WONG, Kevin Y.L. YIP, Ka-Fai TO, Alfred S.L. CHENG
Name of ConferenceThe 77th Annual Meeting of the Japanese Cancer Association
Start Date of Conference27/09/2018
End Date of Conference29/09/2018
Place of ConferenceOsaka
Country/Region of ConferenceJapan
Proceedings TitleCancer Science
Volume Number109
Issue NumberSuppl. 2
Pages235 - 235
LanguagesEnglish-United Kingdom

Last updated on 2021-23-11 at 01:09