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

被引:56
作者
Chen, Leilei [1 ]
Hu, Liang [1 ]
Chan, Tim Hon Man [1 ]
Tsao, George Sai-Wah [2 ]
Xie, Dan [5 ]
Huo, Ke-Ke [6 ]
Fu, Li [1 ]
Ma, Stephanie [3 ]
Zheng, Bo-Jian [4 ]
Guan, Xin-Yuan [1 ,5 ]
机构
[1] Univ Hong Kong, Dept Clin Oncol, Pokfulam, Hong Kong, Peoples R China
[2] Univ Hong Kong, Dept Anat, Pokfulam, Hong Kong, Peoples R China
[3] Univ Hong Kong, Dept Pathol, Pokfulam, Hong Kong, Peoples R China
[4] Univ Hong Kong, Dept Microbiol, Pokfulam, Hong Kong, Peoples R China
[5] Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol So China, Guangzhou 510275, Guangdong, Peoples R China
[6] Fudan Univ, Inst Genet, State Key Lab Genet Engn, Shanghai 200433, Peoples R China
关键词
COMPARATIVE GENOMIC HYBRIDIZATION; SYNTHETIC RETINOIDS; CYTOCHROME-C; APOPTOSIS; RECEPTORS; INDUCTION; CASPASE-9; RELEASE;
D O I
10.1002/hep.22933
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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;50:122-129.)
引用
收藏
页码:122 / 129
页数:8
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