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.
© 2015 The Authors.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Binding Sites
-
Cell Cycle Proteins
-
Cell Line
-
Cell Proliferation
-
Citric Acid Cycle / genetics
-
Enzyme Activation
-
Epithelial Cells / cytology
-
Epithelial Cells / metabolism
-
Forkhead Box Protein O1
-
Forkhead Box Protein O3
-
Forkhead Transcription Factors / genetics
-
Forkhead Transcription Factors / metabolism*
-
Gene Expression Regulation, Neoplastic*
-
Glutarates / metabolism
-
HeLa Cells
-
Histone Demethylases / genetics
-
Histone Demethylases / metabolism
-
Humans
-
Introns
-
Isocitrate Dehydrogenase / genetics
-
Isocitrate Dehydrogenase / metabolism*
-
Ketoglutaric Acids / metabolism
-
NADP / metabolism
-
Protein Binding
-
Signal Transduction
-
Transcription Factors / genetics
-
Transcription Factors / metabolism*
-
Transcription, Genetic
Substances
-
Cell Cycle Proteins
-
FOXO1 protein, human
-
FOXO3 protein, human
-
FOXO4 protein, human
-
Forkhead Box Protein O1
-
Forkhead Box Protein O3
-
Forkhead Transcription Factors
-
Glutarates
-
Ketoglutaric Acids
-
Transcription Factors
-
alpha-hydroxyglutarate
-
NADP
-
Isocitrate Dehydrogenase
-
IDH1 protein, human
-
Histone Demethylases