FOXO3a regulates glycolysis via transcriptional control of tumor suppressor TSC1.
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.
Khatri
Shikha
S
Department of Cancer and Cell Biology, University of Cincinnati, Cincinnati, Ohio 45267, USA.
Yepiskoposyan
Hasmik
H
Gallo
Catherine A
CA
Tandon
Preeti
P
Plas
David R
DR
D000818:Animals; D002460:Cell Line; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics
C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D007166:Immunosuppressive Agents; D046912:Multiprotein Complexes; D011506:Proteins; C000624650:TSC1 protein, human; D014157:Transcription Factors; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus