FOXOs support the metabolic requirements of normal and tumor cells by promoting IDH1 expression

FOXO transcription factors are considered bona fide tumor suppressors; however, recent studies showed FOXOs are also required for tumor survival. Here, we identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α‐ketoglutarate and NADPH. In cancer cells carrying mutant IDH1, FOXOs likewise stimulate mutant IDH1 expression and maintain the levels of the oncometabolite 2‐hydroxyglutarate, which stimulates cancer cell proliferation and inhibits TET enzymes and histone demethylases. Combined, our data provide a new paradigm for the paradoxical role of FOXOs in both tumor suppression and promotion. Synopsis FOXO transcription factors promote the expression of wild‐type and mutant IDH1 and thus increase the levels of α‐KG and the oncometabolite 2‐HG. FOXOs thereby support key metabolic requirements of normal and cancer cells. The wild‐type and mutant IDH1 gene are direct transcriptional targets of FOXO. FOXOs increase the levels of α‐ketoglutarate and the oncometabolite 2‐hydroxyglutarate. FOXOs and IDH1 maintain histone and DNA methylation in a similar manner. Graphical Abstract FOXO transcription factors promote the expression of wild‐type and mutant IDH1 and thus increase the levels of α‐KG and the oncometabolite 2‐HG. FOXOs thereby support key metabolic requirements of normal and cancer cells.