TY - JOUR

T1 - FoxO3A promotes metabolic adaptation to hypoxia by antagonizing Myc function

AU - Jensen, Kim Steen

AU - Binderup, Tina

AU - Jensen, Klaus Thorleif

AU - Therkelsen, Ib

AU - Borup, Rehannah

AU - Nilsson, Elise

AU - Multhaupt, Hinke

AU - Bouchard, Caroline

AU - Quistorff, Bjørn

AU - Kjaer, Andreas

AU - Landberg, Göran

AU - Staller, Peter

PY - 2011/11/16

Y1 - 2011/11/16

N2 - 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.

AB - 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.

KW - Adaptation, Physiological

KW - Animals

KW - Carcinoma, Intraductal, Noninfiltrating

KW - Cell Hypoxia

KW - Cell Line, Tumor

KW - Cell Survival

KW - Forkhead Transcription Factors

KW - Genes, Mitochondrial

KW - Glycolysis

KW - HeLa Cells

KW - Humans

KW - Hypoxia-Inducible Factor 1, alpha Subunit

KW - Mice

KW - Mice, Nude

KW - Mitochondria

KW - Neoplasm Transplantation

KW - Oxygen

KW - Oxygen Consumption

KW - Proto-Oncogene Proteins c-myc

KW - RNA Interference

KW - RNA, Small Interfering

KW - Reactive Oxygen Species

KW - Stress, Physiological

KW - Transplantation, Heterologous

U2 - 10.1038/emboj.2011.323

DO - 10.1038/emboj.2011.323

M3 - Journal article

C2 - 21915097

VL - 30

SP - 4554

EP - 4570

JO - E M B O Journal

JF - E M B O Journal

SN - 0261-4189

IS - 22

ER -