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


摘要Aberrant 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.
著者Myth 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
會議名稱The 77th Annual Meeting of the Japanese Cancer Association
會議論文集題名Cancer Science
期次Suppl. 2
頁次235 - 235

上次更新時間 2021-02-12 於 00:37