S-nitrosylation from GSNOR deficiency impairs DNA repair and promotes hepatocarcinogenesis

Sci Transl Med. 2010 Feb 17;2(19):19ra13. doi: 10.1126/scitranslmed.3000328.

Abstract

Human hepatocellular carcinoma (HCC) is associated with elevated expression of inducible nitric oxide synthase (iNOS), but the role of nitric oxide in the pathogenesis of HCC remains unknown. We found that the abundance and activity of S-nitrosoglutathione reductase (GSNOR), a protein critical for control of protein S-nitrosylation, were significantly decreased in approximately 50% of patients with HCC. GSNOR-deficient mice were very susceptible to spontaneous and carcinogen-induced HCC. During inflammatory responses, the livers of GSNOR-deficient mice exhibited substantial S-nitrosylation and proteasomal degradation of the key DNA repair protein O(6)-alkylguanine-DNA alkyltransferase. As a result, repair of carcinogenic O(6)-alkylguanines in GSNOR-deficient mice was significantly impaired. Predisposition to HCC, S-nitrosylation and depletion of alkylguanine-DNA alkyltransferase, and accumulation of O(6)-alkylguanines were all abolished in mice deficient in both GSNOR and iNOS. Thus, our data suggest that GSNOR deficiency, through dysregulated S-nitrosylation, may promote HCC, possibly by inactivating a DNA repair system.

MeSH terms

  • Aldehyde Oxidoreductases / deficiency*
  • Aldehyde Oxidoreductases / genetics
  • Aldehyde Oxidoreductases / metabolism*
  • Animals
  • Carcinoma, Hepatocellular / physiopathology*
  • DNA Repair*
  • Female
  • Gene Deletion
  • Humans
  • Liver / metabolism
  • Liver / pathology
  • Liver Neoplasms / physiopathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism
  • O(6)-Methylguanine-DNA Methyltransferase / genetics
  • O(6)-Methylguanine-DNA Methyltransferase / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • S-Nitrosothiols / metabolism
  • Survival Rate

Substances

  • S-Nitrosothiols
  • Nitric Oxide Synthase Type II
  • Aldehyde Oxidoreductases
  • formaldehyde dehydrogenase, glutathione-independent
  • O(6)-Methylguanine-DNA Methyltransferase
  • Proteasome Endopeptidase Complex