Chromodomain helicase/adenosine triphosphatase DNA binding... : Hepatology (original) (raw)

Hepatobiliary Malignancies

Chromodomain helicase/adenosine triphosphatase DNA binding protein 1–like (CHD1l) gene suppresses the nucleus-to-mitochondria translocation of nur77 to sustain hepatocellular carcinoma cell survival#

Chen, Leilei1; Hu, Liang1; Chan, Tim Hon Man1; Tsao, George Sai-Wah2; Xie, Dan3; Huo, Ke-Ke4; Fu, Li1; Ma, Stephanie5; Zheng, Bo-Jian6; Guan, Xin-Yuan1,3*†

1 Department of Clinical Oncology, The University of Hong Kong, Pokfulam, Hong Kong, China

2 Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong, China

3 Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong, China

4 Department of Microbiology, The University of Hong Kong, Pokfulam, Hong Kong, China

5 State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou, China

6 State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University, Shanghai, China

* Department of Clinical Oncology, The University of Hong Kong, Room L10-56, Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong

Email:[email protected]

Received January 9, 2009; accepted February 23, 2009.

Published online 3 March 2009 in Wiley InterScience (www.interscience.wiley.com).

Grant sponsor: Hong Kong Research Grant Council; Grant Number: HKU 7393/04M; Grant sponsor: Hong Kong Research Grant Council Central Allocation; Grant Number: HKU 1/06C; Grant sponsor: “Hundred Talents Program” at Sun Yat-Sen University; Grant Number: 85000-3171311; Grant sponsor: Major State Basic Research Program of China; Grant Number: 2006CB910104; Grant sponsor: Foundation of Guangzhou Science and Technology Bureau; Grant Number: 2005Z1-E0131.

# Potential conflict of interest: Nothing to report.

† fax: (852)-28169126

Additional Supporting Information may be found in the online version of this article.

Abstract

Amplification of 1q21 has been detected in 58% to 78% of primary hepatocellular carcinoma cases, suggesting that one or more oncogenes within the amplicon play a critical role in the development of this disease. The chromodomain helicase/adenosine triphosphatase DNA binding protein 1–like gene (CHD1L) is a recently identified oncogene localized at 1q21. Our previous studies have demonstrated that CHD1L has strong tumorigenic ability and confers high susceptibility to spontaneous tumors in a _CHD1L_-transgenic mouse model. In this study, we demonstrate that the antiapoptotic ability of CHD1L is associated with its interaction with Nur77, a critical member of a p53-independent apoptotic pathway. As the first cellular protein identified to bind Nur77, CHD1L is able to inhibit the nucleus-to-mitochondria translocation of Nur77, which is the key step of Nur77-mediated apoptosis, resulting in the hindrance of the release of cytochrome c and the initiation of apoptosis. Knock-down of CHD1L expression by RNA interference could rescue the mitochondrial targeting of Nur77 and the subsequent apoptosis. Further studies found that the 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 that the inhibition of Nur77-mediated apoptosis by endogenous CHD1L is a critical biological cellular process in hepatocarcinogenesis. Conclusion: We demonstrate in this study that overexpression of CHD1L could sustain tumor cell survival by preventing Nur77-mediated apoptosis. (Hepatology 2009.)