Biotech Research and Innovation Centre, University of Copenhagen, Denmark.
EMBO J. 2011 Nov 16;30(22):4554-70. doi: 10.1038/emboj.2011.323.
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.
后生动物暴露于缺氧环境中会引发代谢转换，这种转换是由缺氧诱导因子 1（HIF-1）协调的。HIF-1 介导糖酵解的诱导和线粒体呼吸的主动抑制，从而减少氧气消耗并抑制潜在有害的活性氧（ROS）的产生。在这里，我们表明 FoxO3A 在 HIF-1 下游的缺氧环境中被激活，并介导了一组核编码的线粒体基因的缺氧抑制。FoxO3A 是缺氧抑制线粒体质量、耗氧量和 ROS 产生所必需的，并且促进缺氧条件下细胞的存活。FoxO3A 被募集到核编码的线粒体基因的启动子上，通过一种不依赖于结合共识 FoxO 识别元件的机制，直接拮抗 c-Myc 功能。此外，我们表明 FoxO3A 在体内人类缺氧肿瘤组织中被激活，并且表达 FoxO3A 短发夹 RNA（shRNA）的异种移植肿瘤在大小和代谢上都发生了变化。我们的研究结果定义了 FoxO3A 在缺氧环境中促进代谢适应和应激抗性的新机制。
