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. 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.