FOXO3a Regulates Glycolysis via Transcriptional Control of Tumor Suppressor TSC1

• Published in: The Journal of biological chemistry 2010-05, Vol.285 (21), p.15960-15965
• Main Authors: Khatri, Shikha, Yepiskoposyan, Hasmik, Gallo, Catherine A., Tandon, Preeti, Plas, David R.
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Forkhead Box Protein O3; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; FOXO; FOXO3a; Glucose; Glycolysis; Glycolysis - drug effects; Glycolysis - physiology; Humans; Immunosuppressive Agents - pharmacology; Mechanistic Target of Rapamycin Complex 1; Metabolic Regulation; Metabolism; Mice; mTOR; Multiprotein Complexes; Phosphorylation - drug effects; Phosphorylation - physiology; Promoter Regions, Genetic - physiology; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Rapamycin; Ribosomal Protein S6 Kinases - genetics; Ribosomal Protein S6 Kinases - metabolism; Signal Transduction; Sirolimus - pharmacology; TOR Serine-Threonine Kinases; Transcription; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic - drug effects; Transcription, Genetic - physiology; Transcriptional Activation - drug effects; Transcriptional Activation - physiology; TSC1; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Proteins - biosynthesis; Tumor Suppressor Proteins - genetics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.121871

Akt signal transduction induces coordinated increases in glycolysis and apoptosis resistance in a broad spectrum of cancers. Downstream of Akt, the FoxO transcription factors regulate apoptosis via Bim, but the contributions of FoxOs in regulating Akt-induced glycolysis are not well described. We find that FoxO3a knockdown is sufficient to induce apoptosis resistance in conjunction with elevated glycolysis. Glycolysis in FoxO3a-deficient cells was associated with increased S6K1 phosphorylation and was sensitive to rapamycin, an inhibitor of the mTORC1 pathway that has been linked to glycolysis regulation. We show that mTORC1-dependent glycolysis is increased in FoxO3a knockdown cells due to decreased expression of the TSC1 tumor suppressor that opposes mTORC1 activation. FoxO3a binds to and transactivates the TSC1 promoter, indicating a key role for FoxO3a in regulating TSC1 expression. Together, these data demonstrate that FoxO3a regulates glycolysis downstream of Akt through transcriptional control of Tsc1.