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

Hepatology. 2009 Jul;50(1):122-9. doi: 10.1002/hep.22933.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / physiology
  • Carcinoma, Hepatocellular / enzymology*
  • Carcinoma, Hepatocellular / pathology*
  • Cell Nucleus*
  • Cell Survival / genetics
  • DNA Helicases / genetics*
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Liver Neoplasms / enzymology*
  • Liver Neoplasms / pathology*
  • Mitochondria*
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Protein Transport*
  • Receptors, Steroid / metabolism*


  • DNA-Binding Proteins
  • NR4A1 protein, human
  • Nr4a1 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Receptors, Steroid
  • Adenosine Triphosphatases
  • DNA Helicases
  • CHD1 protein, human