Abstract 868: Epigenomic profiling of primary hepatocellular carcinoma reveals super-enhancer-associated chromatin regulator network

Abstract

Abstract 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 modifications 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 fulfill 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 modifications in NAFLD-associated HCC development, nanoscale chromatin immunoprecipitation sequencing of multiple histone marks were performed. By integrating multiple epigenomic profiles from primary NAFLD-associated HCCs and matched non-tumor tissues, we identified recurrent SEs enriched that contribute to fatty liver, lipid metabolism and metabolic syndrome. Interestingly, we observed significant 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 significantly 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 NAFLD-associated HCCs. Citation Format: 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. Epigenomic profiling of primary hepatocellular carcinoma reveals super-enhancer-associated chromatin regulator network [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 868.