TRAP1 and SDH as therapeutic targets of HCC.

S-nitrosoglutathione reductase (GSNOR) represents the best-documented denitrosylase implicated in regulating the levels of proteins post-translationally modified by nitric oxide (NO) on cysteine residues by S-nitrosylation. GSNOR controls a diverse array of physiological functions, including cellular growth and differentiation, inflammation and metabolism. Chromosomal deletion of GSNOR results in pathological protein S-nitrosylation that is implicated in human hepatocellular carcinoma (HCC). Here we identify a metabolic hallmark of aberrant S-nitrosylation in HCC and exploit it for therapeutic gain. We find that hepatocyte GSNOR deficiency is characterized by mitochondrial alteration and by marked increases in succinate dehydrogenase (SDH) levels and activity. We find that this depends on the selective S-nitrosylation of Cys501 in the mitochondrial chaperone TRAP1, which mediates its degradation. As a result, GSNOR-deficient cells and tumors are highly sensitive to SDH inhibition, namely to α-tocopheryl succinate, an SDH-targeting molecule that induced RIP1/PARP1-mediated necroptosis and inhibited tumor growth. Our work provides a specific molecular signature of aberrant S-nitrosylation in HCC and thereby a novel molecular target in SDH, and a first-in-class therapy to treat the disease.

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