Emerging roles of hypoxia-inducible factors and reactive oxygen species in cancer and pluripotent stem cells

Abstract

Eukaryotic organisms require oxygen homeostasis to maintain proper cellular function for survival. During conditions of low oxygen tension (hypoxia), cells activate the transcription of genes that induce an adaptive response, which supplies oxygen to tissues. Hypoxia and hypoxia-inducible factors (HIFs) may contribute to the maintenance of putative cancer stem cells, which can continue self-renewal indefinitely and express stemness genes in hypoxic stress environments (stem cell niches). Reactive oxygen species (ROS) have long been recognized as toxic by-products of aerobic metabolism that are harmful to living cells, leading to DNA damage, senescence, or cell death. HIFs may promote a cancer stem cell state, whereas the loss of HIFs induces the production of cellular ROS and activation of proteins p53 and p16(Ink4a), which lead to tumor cell death and senescence. ROS seem to inhibit HIF regulation in cancer cells. By contrast, controversial data have suggested that hypoxia increases the generation of ROS, which prevents hydroxylation of HIF proteins by inducing their transcription as negative feedback. Moreover, hypoxic conditions enhance the generation of induced pluripotent stem cells (iPSCs). During reprogramming of somatic cells into a PSC state, cells attain a metabolic state typically observed in embryonic stem cells (ESCs). ESCs and iPSCs share similar bioenergetic metabolisms, including decreased mitochondrial number and activity, and induced anaerobic glycolysis. This review discusses the current knowledge regarding the emerging roles of ROS homeostasis in cellular reprogramming and the implications of hypoxic regulation in cancer development.

Keywords: Cancer; Hypoxia-inducible factor; Reactive oxygen species; Stem cells.

Figure 1

Schematic model showing regulatory mechanism of mitochondrial reactive oxygen species (ROS) and hypoxia‐inducible factor (HIF) in tumor angiogenesis. Under normoxic condition, prolyl‐hydroxylase domain‐containing enzymes (PHD) activity is inhibited by mitochondrial ROS. PHDs and factor inhibiting HIF (FIH) inhibit the expression of HIF‐α subunit. HIF‐α activity is regulated by sirtuin 3 , whereas HIF‐α activity is upregulated by mammalian target of rapamycin (mTOR). Under hypoxic conditions, low ROS levels are maintained by redox homeostasis, which is regulated by the antioxidant enzymatic defense systems through the activity of FoxOs, Ref1, Nrf2, and ataxia telangiectasia mutated (ATM). HIF‐α stabilization results in the expression of HIF target genes, such as vascular endothelial growth factor (VEGF) and erythropoietin (EPO), with effects on metabolism, tumor angiogenesis, redox homeostasis.

Figure 2

Schematic representation of the roles of reactive oxygen species (ROS) and hypoxia‐inducible factor (HIF) in reprogramming to induced pluripotent stem cells (iPSCs) under hypoxic condition. In the early stage of reprogramming, activities of ROS and mitochondrial (mt) DNA are high. Then, through the activation of HIF‐1α and HIF‐2α under hypoxic conditions, expression of internal stemness genes and antioxidant enzymes increases and that of p53 deceases. Simultaneously, activities of mt DNA, HIF‐2α, and ROS signaling decrease. In the late stage of reprogramming to iPSCs, the metabolic switch occurs toward anaerobic glycolysis. The tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) represses the process of iPSC reprogramming. ATM = ataxia telangiectasia mutated.