CHD1L suppresses the nucleus-to-mitochondria translocation of Nur77 to sustain hepatocellular carcinoma cell survival

Abstract

Chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L), also named amplified in liver cancer 1 (ALC1), is a recently identified oncogene localized at 1q21, one of the most frequently amplified chromosomal regions in hepatocellular carcinoma (HCC). Our previous studies demonstrated that CHD1L confers high susceptibility to spontaneous hepatocarcinogenesis and HCC formation and development, lending a support to our hypothesis that CHD1L is the target oncogene responsible for the 1q21 amplification event. Recenly, by yeast-two hybrid assay, a key apoptosis mediator Nur77 was revealed to bind CHD1L. In this study, as the first cellular protein identified to bind Nur77, CHD1L are able to inhibit the nucleus-to-mitochondria translocation of Nur77, resulting in the hinderance of cytochrome c (Cyt c) release and the subsequent caspase activation and apoptosis. Further studies found that C-terminal Macro domain of CHD1L is responsible for the interaction with Nur77, and a CHD1L mutant lacking residues 600-897 failed to interact with Nur77 and prevented Nur77-mediated apoptosis. More importantly, we found there existed a reverse correlation between CHD1L expression level and the rate of apoptosis among eight HCC cell lines and two normal liver cell lines, and the nucleus-to-mitochondria translocation of Nur77 was inhibited in HepG2 cells with the high level of endogenous CHD1L expression, suggesting the inhibition of Nur77-mediated apoptosis by endogenous CHD1L is a critical biological process in hepatocarcinogenesis. Overall, the mechanistic study on CHD1L defines a novel pathway in HCC progression to enhance cell survival by preventing Nur77-mediated apoptosis, which could be suggested as the reason for CHD1L oncogenicity and used as great implications for HCC therapeutics.