Research ArticleLiver Cancer

S-Nitrosylation from GSNOR Deficiency Impairs DNA Repair and Promotes Hepatocarcinogenesis

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Science Translational Medicine  17 Feb 2010:
Vol. 2, Issue 19, pp. 19ra13
DOI: 10.1126/scitranslmed.3000328

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Saying NO to Liver Cancer

Years ago, workers at Alfred Nobel’s factory who made dynamite from nitroglycerin exhibited two puzzling symptoms: severe headaches and, for those suffering from angina, relief from chest pain. It was not until the early 1980s that the reason for this became clear. The body converts nitroglycerin fumes to nitric oxide (NO), and as a result of its actions, blood vessels dilate, causing headaches and reducing the heart’s workload. Such groundbreaking discoveries about NO inspired a flood of new research. Today we know that this simple molecule, which is synthesized enzymatically by some cells, plays key roles in numerous biological processes—and in a wide spectrum of diseases. Now, Liu and co-workers describe results that tie dysregulation of one NO-related process to liver cancer.

S-nitrosylation—a posttranslational protein modification in which a nitroso (NO) group is attached to a cysteine residue—can affect the target protein’s behavior and represents one means by which NO influences cell function. Dysregulation of S-nitrosylation can occur because of alterations in the enzymes that produce NO, the NO synthases (NOSs), or in those that remove NO groups, such as S-nitrosoglutathione reductase (GSNOR). Increased inducible NOS (iNOS), which produces NO in inflammatory conditions, is associated with conditions such as chronic viral hepatitis that predispose to human hepatocellular carcinoma (HCC). How NO might contribute to the pathogenesis of this liver cancer, however, was unknown.

Liu and colleagues found that GSNOR activity was substantially reduced in HCC (relative to noncancerous liver tissue) from about half of the patients they tested; a possible explanation is that the chromosomal region that includes the gene encoding GSNOR is often deleted in HCC. Moreover, the researchers determined that mice that lack GSNOR are prone to developing this form of cancer spontaneously—a tendency that is abolished if the mice also lack iNOS. The mice without GSNOR were also more susceptible to liver cancer induced by a carcinogen that causes a specific type of DNA lesion, which is normally fixed by the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AGT). After carcinogen exposure, the mice without GSNOR had much less AGT in their livers, and displayed impaired DNA repair, relative to wild-type mice. Treatment with an inflammatory agent also caused AGT levels to fall precipitously in the mouse livers lacking GSNOR (a proteasome-mediated reaction), but not if they also lacked iNOS, indicating that GSNOR protects AGT from nitrosative stress. Finally, the researchers showed that AGT is a direct target of S-nitrosylation in vivo, and that the amount of S-nitrosylated AGT is increased in the absence of GSNOR. Thus, dysregulated S-nitrosylation could possibly inactivate the AGT DNA repair system and promote HCC. If verified, such a mechanism could potentially explain the tens of thousands of mutations that are observed in cancer cells—and inhibition of S-nitrosylation in patients with GSNOR deficiency might be one way to say NO to liver cancer, a deadly disease with few effective treatments.


  • Citation: W. Wei, B. Li, M. A. Hanes, S. Kakar, X. Chen, L. Liu, S-Nitrosylation from GSNOR Deficiency Impairs DNA Repair and Promotes Hepatocarcinogenesis. Sci. Transl. Med. 2, 19ra13 (2010).

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