HELLS regulates chromatin remodeling and epigenetic silencing of multiple tumor suppressor genes in human hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the third lethal cancer worldwide. Increasing evidence showed that epigenetic alterations play an important role in human carcinogenesis. Deregulation of DNA methylation and histone modifications have recently been characterized in HCC, but the significance of chromatin remodeling in liver carcinogenesis remains to be explored. In this study, by systematically analyzing the expression of chromatin remodeling genes in human HCCs, we found that HELicase, Lymphoid‐Specific (HELLS), a SWI2/SNF2 chromatin remodeling enzyme, was remarkably overexpressed in HCC. Overexpression of HELLS correlated with more aggressive clinicopathological features and poorer patient prognosis, compared to those patients with lower HELLS expression. We further showed that up‐regulation of HELLS in HCC was conferred by hyperactivation of transcription factor SP1. To investigate the functions of HELLS in HCC, we generated both gain‐ and loss‐of‐function models by CRISPR activation system, lentiviral shRNA, and CRISPR/Cas9 genome editing system. We demonstrated that overexpression of HELLS augmented HCC cell proliferation and migration. In contrast, depletion of HELLS reduced HCC growth and metastasis both in vitro and in vivo. Moreover, inactivation of HELLS led metabolic reprogramming and reversed Warburg effect in HCC cells. Mechanistically, by integrating analysis of RNA‐seq and MNase‐seq, we revealed that overexpression of HELLS increased nucleosome occupancy that obstructed the accessibility of enhancers and hindered the formation of nucleosome‐free region (NFR) at transcription start site (TSS). Though this mechanism, up‐regulation of HELLS mediated epigenetic silencing of multiple tumor suppressor genes including E‐Cadherin, FBP1, IGFBP3, XAF1 and CREB3L3 in HCC.

Conclusion

Our data unravel that HELLS is a key epigenetic driver of HCC. By altering the nucleosome occupancy at NFR and enhancer, HELLS epigenetically suppresses multiple tumor suppressor genes to promote HCC progression.

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