title: mTOR complex 2 controls glycolytic metabolism in glioblastoma through FoxO acetylation and upregulation of c-Myc.
abstract: 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.
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Kenta
authors.initials: K
authors.lastname: Masui
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tanaka
authors.forename: David
authors.initials: D
authors.lastname: Akhavan
authors.forename: Ivan
authors.initials: I
authors.lastname: Babic
authors.forename: Beatrice
authors.initials: B
authors.lastname: Gini
authors.forename: Tomoo
authors.initials: T
authors.lastname: Matsutani
authors.forename: Akio
authors.initials: A
authors.lastname: Iwanami
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.forename: Genaro R
authors.initials: GR
authors.lastname: Villa
authors.forename: Yuchao
authors.initials: Y
authors.lastname: Gu
authors.forename: Carl
authors.initials: C
authors.lastname: Campos
authors.forename: Shaojun
authors.initials: S
authors.lastname: Zhu
authors.forename: Huijun
authors.initials: H
authors.lastname: Yang
authors.forename: William H
authors.initials: WH
authors.lastname: Yong
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.forename: Ingo K
authors.initials: IK
authors.lastname: Mellinghoff
authors.forename: Webster K
authors.initials: WK
authors.lastname: Cavenee
authors.forename: Reuben J
authors.initials: RJ
authors.lastname: Shaw
authors.forename: Paul S
authors.initials: PS
authors.lastname: Mischel
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D005947:Glucose; D006655:Histone Deacetylases; D000076225:Mechanistic Target of Rapamycin Complex 2; D035683:MicroRNAs; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc; D058570:TOR Serine-Threonine Kinases; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; C522425:MIRN34 microRNA, human