mTORC2 is required for the growth of GBM cells in glucose
•
mTORC2 controls glycolytic metabolism by regulating the cellular level c-Myc
•
mTORC2 signaling acetylates FoxO1 and FoxO3 to upregulate c-Myc
•
mTORC2, acetylated FoxO, and c-Myc axis confer shorter survival in patients
Summary
Aerobic glycolysis (the Warburg effect) is a core hallmark of cancer, but the molecular mechanisms underlying it remain unclear. Here, we identify an unexpected central role for mTORC2 in cancer metabolic reprogramming where it controls glycolytic metabolism by ultimately regulating the cellular level of c-Myc. We show that mTORC2 promotes inactivating phosphorylation of class IIa histone deacetylases, which leads to the acetylation of FoxO1 and FoxO3, and this in turn releases c-Myc from a suppressive miR-34c-dependent network. These central features of activated mTORC2 signaling, acetylated FoxO, and c-Myc levels are highly intercorrelated in clinical samples and with shorter survival of GBM patients. These results identify a specific, Akt-independent role for mTORC2 in regulating glycolytic metabolism in cancer.
