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Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is caused by loss of function mutations in fumarate hydratase (FH) and results in an aggressive subtype of renal cell carcinoma with limited treatment options. FH loss results in accumulation of fumarate, an oncometabolite that inhibits alpha ketoglutarate-dependent dioxygenases and leads to global DNA hypermethylation. Noronha and colleagues found that hypermethylation in FH-deficient samples is associated with silencing of nicotinate phosphoribosyl transferase (NAPRT), which encodes a rate-limiting enzyme in NAD⁺ biosynthesis. FH-deficient RCC models with loss of NAPRT expression, and other oncometabolite-producing cancers with NAPRT loss, were highly sensitive to nicotinamide phosphoribosyl transferase inhibitors (NAMPTis). Furthermore, synergistic cytotoxicity with combined inhibition of poly (ADP-ribose) PARP and NAMPT was observed in cells with NAPRT expression loss, likely due to increased impairment of PAR-mediated DNA repair from NAD⁺ depletion. In sum, this study uncovers how oncometabolite-associated hypermethylation can lead...