title: FOXOs support the metabolic requirements of normal and tumor cells by promoting IDH1 expression.
abstract: 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.
authors: Department of Molecular Cancer Research, University Medical Center Utrecht, CG Utrecht, The Netherlands.
authors: Paraskevi
authors: P
authors: Charitou
authors: Department of Molecular Cancer Research, University Medical Center Utrecht, CG Utrecht, The Netherlands.
authors: Maria
authors: M
authors: Rodriguez-Colman
authors: Department of Medical Genetics, UMC Utrecht, Utrecht, The Netherlands.
authors: Johan
authors: J
authors: Gerrits
authors: Department of Molecular Cancer Research, University Medical Center Utrecht, CG Utrecht, The Netherlands.
authors: Miranda
authors: M
authors: van Triest
authors: Department of Molecular Cancer Research, University Medical Center Utrecht, CG Utrecht, The Netherlands.
authors: Marian
authors: M
authors: Groot Koerkamp
authors: Department of Molecular Cancer Research, University Medical Center Utrecht, CG Utrecht, The Netherlands.
authors: Marten
authors: M
authors: Hornsveld
authors: Department of Molecular Cancer Research, University Medical Center Utrecht, CG Utrecht, The Netherlands.
authors: Frank
authors: F
authors: Holstege
authors: Department of Medical Genetics, UMC Utrecht, Utrecht, The Netherlands.
authors: Nanda M
authors: NM
authors: Verhoeven-Duif
authors: Department of Molecular Cancer Research, University Medical Center Utrecht, CG Utrecht, The Netherlands b.m.t.burgering@umcutrecht.nl.
authors: Boudewijn M T
authors: BM
authors: Burgering
mesh_terms: D001665:Binding Sites; D018797:Cell Cycle Proteins; D002460:Cell Line; D049109:Cell Proliferation; D002952:Citric Acid Cycle / Q000235:genetics; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005977:Glutarates / Q000378:metabolism; D006367:HeLa Cells; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007438:Introns; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D007656:Ketoglutaric Acids / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D018797:Cell Cycle Proteins; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; C108803:FOXO4 protein, human; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D005977:Glutarates; D007656:Ketoglutaric Acids; D014157:Transcription Factors; C019417:alpha-hydroxyglutarate; D009249:NADP; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D056466:Histone Demethylases
keywords: FOXO; IDH1; PI3K; oncometabolite
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