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 shorthairpin 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.

Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase

“…They left open, however, the possibility that regulation of FOXO3a abundance by EglN2 is an indirect consequence of activating HIF, which is the canonical EglN substrate, instead of, or in addition to, changes in FOXO3a hydroxylation. A link between HIF and hypoxic induction of FOXO3a has been suggested before (Bakker et al 2007;Jensen et al 2011). To address this, we infected T47D or BT474 breast cancer cells with shRNAs against ARNT, the critical binding partner for HIFa's transcriptional activity.…”

“…In addition, FOXO3a appears to be a direct HIF target (Bakker et al 2007;Jensen et al 2011). FOXO3a clearly plays a role in adaptation to hypoxic stress (Scott et al 2002;Miyamoto et al 2007;Tothova and Gilliland 2007;Mabon et al 2009;Jensen et al 2011). Induction of FOXO3a by hypoxia might help conserve ATP by restricting cell proliferation as well as by reprogramming cell metabolism.…”

Zebrafish foxo3b Negatively Regulates Antiviral Response through Suppressing the Transactivity of irf3 and irf7

“…Among the four FOXO genes, FOXO3 has been the most widely investigated. As a transcription factor, FOXO3 regulates expression of several target genes that participate in a series of cellular processes and respond to various cellular stresses (4)(5)(6)(7)(8). Alternatively, different cellular stresses cause variant statuses of posttranslational modifications of FOXO3, such as phosphorylation, ubiquitination, acetylation, and methylation, which in turn regulate the stability or activity of FOXO3 (9)(10)(11)(12)(13)(14).…”

Mitophagy in hematopoietic stem cells

“…[39][40][41] By contrast, FOXO family member FOXO3 is activated downstream of HIF1A [hypoxia inducible factor 1, α subunit (basic helix-loop-helix transcription factor)] during hypoxic conditions and represses a set of nuclear-encoded mitochondrial genes that mediate the hypoxic suppression of mitochondrial mass, oxygen consumption, and ROS production. 42 FOXO-deficient mice (either Foxo1/3/4-null or Foxo3/Foxo3a-null) have elevated levels of ROS, which are associated with defects in HSCs' reconstitution capability. These defects can be reversed by antioxidant treatment, implicating excessive ROS production as a detrimental signal for HSCs' function and survival.…”