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FoxO3A promotes metabolic adaptation to hypoxia by antagonizing Myc function
Author(s) -
Jensen Kim Steen,
Binderup Tina,
Jensen Klaus Thorleif,
Therkelsen Ib,
Borup Rehannah,
Nilsson Elise,
Multhaupt Hinke,
Bouchard Caroline,
Quistorff Bjørn,
Kjær Andreas,
Landberg Göran,
Staller Peter
Publication year - 2011
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2011.323
Subject(s) - biology , hypoxia (environmental) , adaptation (eye) , function (biology) , microbiology and biotechnology , computational biology , neuroscience , oxygen , chemistry , organic chemistry
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.