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EMBO Rep. 2015 Apr;16(4):456-66. doi: 10.15252/embr.201439096. Epub 2015 Feb 3.

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

Author information

1
Department of Molecular Cancer Research, University Medical Center Utrecht, CG Utrecht, The Netherlands.
2
Department of Medical Genetics, UMC Utrecht, Utrecht, The Netherlands.
3
Department of Molecular Cancer Research, University Medical Center Utrecht, CG Utrecht, The Netherlands b.m.t.burgering@umcutrecht.nl.

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.

KEYWORDS:

FOXO; IDH1; PI3K; oncometabolite

PMID:
25648147
PMCID:
PMC4388612
DOI:
10.15252/embr.201439096
[Indexed for MEDLINE]
Free PMC Article

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