Epigenomic profiling of primary hepatocellular carcinoma reveals super-enhancer-associated chromatin regulator network
Refereed conference paper presented and published in conference proceedings


摘要Hepatocellular carcinoma (HCC) is the second most common cause of cancer mortality worldwide. Parallel with the growing epidemics of obesity and diabetes, non-alcoholic fatty liver disease (NAFLD) has become the predominant cause leading to HCC in a dysregulated metabolic background. Recent HCC genomics studies present only a paucity of recurrent gene mutations, which lead to a sparkling interest in the epigenetic regulation of hepatic carcinogenesis. Chromatin modifıcations convert the metabolic insults from NAFLD to transcriptional program that contributes to HCC development. Super-enhancers (SEs) are subclass of regulatory elements with unusually strong enrichment for the binding of transcriptional coactivators to fulfıll cell identity. Currently, it has been proposed that dysregulation of SEs underlies the development of diseases including cancers, but the role of SEs in NAFLD-associated HCC is still unknown.
In order to investigate the alterations of histone modifıcations in NAFLD-associated HCC development, nanoscale chromatin immunoprecipitation sequencing of multiple histone marks were performed. By integrating multiple epigenomic profıles from primary NAFLD-associated HCCs and matched nontumor tissues, we identifıed recurrent SEs enriched that contribute to fatty liver, lipid metabolism and metabolic syndrome. Interestingly, we observed signifıcant enrichment of recurrent active SEs in a number of target genes. Notably, through CRISPR/Cas9-induced knockout liver cell lines, we showed that deletion of two distinct SE regions signifıcantly reduced the expression of a candidate target gene and attenuated the tumorigenic potential of HCC cells. In summary, our results show that the dysregulation of SEs contributes to human hepatic carcinogenesis, thus representing novel therapeutic targets for NAFLDassociated HCCs.
著者Liangliang XU, Feng WU, Otto K.W. CHEUNG, Lemuel L.M. SZETO, Myth T.S. MOK, Kevin Y.L. YIP, Ka F. TO, Alfred S.L. CHENG
會議名稱American Association for Cancer Research (AACR) Annual Meeting 2019
會議論文集題名Proceedings of the American Association for Cancer Research
頁次224 - 225

上次更新時間 2019-07-05 於 17:23