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.
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.


CONCLUSIONS
We demonstrate in this study that overexpression of CHD1L could sustain tumor cell survival by preventing Nur77-mediated apoptosis.
Department of Clinical Oncology, The University of Hong Kong, Pokfulam, Hong Kong, China.
Leilei
L
Chen
Liang
L
Hu
Tim Hon Man
TH
Chan
George Sai-Wah
GS
Tsao
Dan
D
Xie
Ke-Ke
KK
Huo
Li
L
Fu
Stephanie
S
Ma
Bo-Jian
BJ
Zheng
Xin-Yuan
XY
Guan
D000251:Adenosine Triphosphatases / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000473:pathology*; D002467:Cell Nucleus; D002470:Cell Survival / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000473:pathology*; D008928:Mitochondria; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D021381:Protein Transport; D011987:Receptors, Steroid / Q000378:metabolism*
D004268:DNA-Binding Proteins; C539821:NR4A1 protein, human; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011987:Receptors, Steroid; D000251:Adenosine Triphosphatases; D004265:DNA Helicases; C080359:CHD1 protein, human