Figure 8.

Alterations in certain metabolic enzymes drive cancer. Mutations in TCA-cycle enzyme succinate dehydrogenase (SDH) and fumarate hydratase (FH) occurs in certain cancers, resulting in accumulation of succinate and fumarate, respectively. Mutations in cytosolic IDH1 or mitochondrial IDH2 occur in certain cancers and cause accumulation of 2-hydroxyglutarate (2HG). Succinate, fumarate, and 2HG inhibit histone demethylases and TET DNA hydoxylases. Succinate and fumarate can activate HIF, whereas R-2HG inhibits HIF. Elevated expression of wild-type phosphoglycerate dehydrogenase (PHGDH) in certain cancers increases serine biosynthesis to fuel one-carbon metabolism necessary for NADPH production and folate intermediates necessary for nucleotide synthesis. (Adapted from Cantor and Sabatini 2012, by permission from the American Association for Cancer Research.)