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

Multicelluar organisms require oxygen homeostasis to maintain proper cellular metabolisms and bioenergetics. However, organisms that tolerate oxygen availability, especially to hypoxia, face the harsh environmental circumstances during their lives. In contrast to an expected strong suppression of protein synthesis, a large number of animals present increased levels of antioxidant defenses during oxygen deprivation. These observations have puzzled us for more than 20 years. Two predominant theories seemed to be irreconcilable: (1) hypoxia would decrease reactive oxygen species (ROS) production (long period), (2) the induction of antioxidant enzymes by hypoxia would require the overproduction of ROS (early period). This induction of antioxidant enzymes during hypoxia was viewed as a way to prepare animals for oxidative damage that may happen ultimately during re-oxygenation. This is a preparation stage for oxidative stress, which idea appeared in 1998.

(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. hypoxia-inducible factors may promote a cancer stem cell state, whereas the loss of hypoxia-inducible factors induces the production of cellular ROS and activation of proteins p53 and p16^Ink4a, which lead to tumor cell death and senescence. Thus, reduced ROS seems to inhibit hypoxia-inducible factors regulation in cancer cells of commit the cell reprogramming of stem cells. However, at the late stage of stress, increased ROS performs the inverted function.

However, many cases of increased oxidative damage in several hypoxia-tolerant organisms under hypoxia. Moreover, over the year, the first idea of assured decrease in ROS under hypoxia was challenged. Instead, recent findings indicate that the production of ROS actually increases in response to hypoxia. Hypoxia increase the generation of ROS, which prevents hydroxylation of hypoxia-inducible factors proteins by inducing their transcription as negative feedback. Moreover, the hypoxic conditions enhance the generation of induced pluripotent stem cells (iPSCs). During reprogramming of somatic cells into a pluripotent stem cell 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. Thus, extent of transition of hypoxia to anoxia might regulate the level of ROS which controlled the converse effects for hypoxia-inducible factors dependent regulation.

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, especially at the long exposure of hypoxia stage. Moreover, the current understanding of emerging insights into the intricate roles and functions of hypoxia-inducible factors and ROS in tumor growth, apoptosis and senescence, and their roles in reprogramming cells into pluripotent stem cells via repression of tumor suppressor genes. Several crucial roles of the hypoxia-inducible factors -signaling in the regulation of stem cell self-renewal and its pluripotency are clarified in this review.