FoxO3A promotes metabolic adaptation to hypoxia by antagonizing Myc function

We show that FoxO3A is activated in hypoxia downstream of Hypoxiainducible factor 1 and mediates the hypoxic repression of a set of nuclear-encoded mitochondrial genes

Kim Steen Jensen; Tina Binderup; Klaus Thorleif Jensen; Ib Therkelsen; Rehannah Borup; Elise Nilsson; Hinke Multhaupt; Caroline Bouchard; Bjørn Quistorff; Andreas Kjaer; Göran Landberg; Peter Staller

2011

Scholarcy highlights

  • In order for metazoan organisms to survive under conditions of low oxygen, a metabolic switch is engaged resulting in the increased conversion of glucose to lactate
  • While FoxO1 and FoxO4 were not regulated in a consistent way by hypoxic treatment or DFO, we found FoxO3A is induced in all tested cell lines and MEFs in hypoxia as well as by DFO
  • The induction of FoxO3A protein and mRNA as determined by qPCR was abrogated by siRNA-mediated knockdown of HIF-1a and to a lesser extent HIF-2a, suggesting that both isoforms contribute to the hypoxic induction
  • Cell fractionation experiments demonstrated that the observed induction of FoxO3A protein in hypoxia was reflective of increases in both the cytosolic and the nuclear compartments
  • We found that the accumulation of FDG relative to the volume of the tumour was significantly impaired for both FoxO3A-KD#1 and FoxO3A-KD#2 xenografts compared with their control counterparts, which could likely be a consequence of their inability to appropriately downregulate mitochondrial activity in hypoxia and shift the balance in favour of glycolysis
  • We have shown that FoxO3A plays an important role in the transcriptional program that facilitates metabolic adaptation in hypoxia
  • The experiments performed in cell culture show an important correlation between dysregulation of metabolism, reactive oxygen species production, and cell death, it should be stressed that we cannot exclude that other hypoxic gene expression changes caused by knockdown of FoxO3A, such as the reduced activation of many hypoxia-induced genes, might contribute to the observed cell and tumour growth phenotypes

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