title: FoxO3A promotes metabolic adaptation to hypoxia by antagonizing Myc function.
abstract: Exposure of metazoan organisms to hypoxia engages a metabolic switch orchestrated by the hypoxia-inducible factor 1 (HIF-1). HIF-1 mediates induction of glycolysis and active repression of mitochondrial respiration that reduces oxygen consumption and inhibits the production of potentially harmful reactive oxygen species (ROS). Here, we show that FoxO3A is activated in hypoxia downstream of HIF-1 and mediates the hypoxic repression of a set of nuclear-encoded mitochondrial genes. FoxO3A is required for hypoxic suppression of mitochondrial mass, oxygen consumption, and ROS production and promotes cell survival in hypoxia. FoxO3A is recruited to the promoters of nuclear-encoded mitochondrial genes where it directly antagonizes c-Myc function via a mechanism that does not require binding to the consensus FoxO recognition element. Furthermore, we show that FoxO3A is activated in human hypoxic tumour tissue in vivo and that FoxO3A short-hairpin RNA (shRNA)-expressing xenograft tumours are decreased in size and metabolically changed. Our findings define a novel mechanism by which FoxO3A promotes metabolic adaptation and stress resistance in hypoxia.
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, Denmark.
authors.forename: Kim Steen
authors.initials: KS
authors.lastname: Jensen
authors.forename: Tina
authors.initials: T
authors.lastname: Binderup
authors.forename: Klaus Thorleif
authors.initials: KT
authors.lastname: Jensen
authors.forename: Ib
authors.initials: I
authors.lastname: Therkelsen
authors.forename: Rehannah
authors.initials: R
authors.lastname: Borup
authors.forename: Elise
authors.initials: E
authors.lastname: Nilsson
authors.forename: Hinke
authors.initials: H
authors.lastname: Multhaupt
authors.forename: Caroline
authors.initials: C
authors.lastname: Bouchard
authors.forename: Bjørn
authors.initials: B
authors.lastname: Quistorff
authors.forename: Andreas
authors.initials: A
authors.lastname: Kjaer
authors.forename: Göran
authors.initials: G
authors.lastname: Landberg
authors.forename: Peter
authors.initials: P
authors.lastname: Staller
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050259:Genes, Mitochondrial; D006019:Glycolysis / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological; D014183:Transplantation, Heterologous
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D010100:Oxygen