Project X1. Hereditary leiomyomatosis and renal cell cancer (HLRCC)

Hereditary leiomyomatosis and renal cell cancer (HLRCC), a hereditary cancer syndrome characterized by the variable development of skin leiomyomas, uterine fibroids, and type 2 papillary renal cell carcinoma (PRCC2), is caused by biallelic inactivation of the gene encoding the Kreb’s cycle enzyme fumarate hydratase (FH). The most immediate consequence of FH inactivation is the accumulation of intracellular fumarate, a thiol-reactive Kreb’s cycle’s metabolite that can form covalent adducts with reactive sulfhydryl groups of biomolecules. We have demonstrated that such covalent adducts are responsible for the sustained activation of the NRF2 (nuclear factor erythroid 2–like 2) transcription factor which thus alters cellular transcriptional programming. In addition, HLRCC-associated cancer cells exhibit a strong Warburg effect phenotype, a hallmark of cancer that is characterized by an increased reliance on glycolysis for energy production, increased fermentation of glucose into lactate, and decreased oxygen consumption. Our current research into this syndrome focuses on identifying the mechanisms by which HLRCC-associated cancer cells acquire the altered metabolic program (Warburg effect phenotype) and the proliferative signal (growth signal).