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

Area of Science:

• Hepatology
• Oncology
• Molecular Biology

Background:

• Hepatocellular carcinoma (HCC) is linked to increased inducible nitric oxide synthase (iNOS), but nitric oxide's role in HCC pathogenesis is unclear.
• S-nitrosoglutathione reductase (GSNOR) regulates protein S-nitrosylation, a critical post-translational modification.

Purpose of the Study:

• To investigate the role of GSNOR and protein S-nitrosylation in hepatocellular carcinoma (HCC) development.
• To determine the impact of GSNOR deficiency on DNA repair mechanisms in the context of HCC.

Main Methods:

• Assessed GSNOR abundance and activity in HCC patient samples.
• Utilized GSNOR-deficient and GSNOR/iNOS double-deficient mouse models.
• Examined the S-nitrosylation and proteasomal degradation of O(6)-alkylguanine-DNA alkyltransferase (AGT).

Main Results:

• GSNOR levels and activity were reduced in approximately 50% of HCC patients.
• GSNOR-deficient mice showed increased susceptibility to spontaneous and carcinogen-induced HCC.
• GSNOR deficiency led to S-nitrosylation and degradation of the DNA repair protein AGT, impairing DNA repair and accumulating DNA damage.
• Absence of iNOS abolished HCC predisposition and AGT dysfunction in GSNOR-deficient mice.

Conclusions:

• GSNOR deficiency promotes HCC development, potentially by disrupting the AGT DNA repair system through dysregulated S-nitrosylation.
• The interplay between GSNOR, iNOS, and AGT is crucial in HCC pathogenesis.
• Targeting GSNOR or modulating S-nitrosylation may represent a therapeutic strategy for HCC.