The Role of Hypoxia-Inducible Factors in Cancer Resistance

Abstract

Diminished oxygen availability (hypoxia) is a hallmark of the tumor microenvironment. A major regulator of cellular adaptation to hypoxia is the hypoxia-inducible factor (HIF) family of transcription factors, which play key roles in many crucial aspects of cancer biology including angiogenesis, stem cell maintenance, metabolic reprogramming, resistance to apoptosis, autocrine growth factor signaling, the EMT program, invasion and metastasis. Resistance to chemotherapy/radiotherapy is the primary cause for treatment failure in clinical oncology. Hypoxia and accumulation of hypoxia-inducible factors (HIFs) in solid tumors have been associated with resistance to treatment and poor prognosis. HIFs causes autophagy establishment to promote survival of cancer cells, and is also associated with the promotion and maintenance of cancer stem cells, a minority subpopulation within the tumor responsible for tumor recurrence and resistance to chemotherapy. In this review, we provide a concise comparative description of the structure, regulation, transcribed genes and roles played by each HIF$α$ subunit in coordinating the transcriptional responses to hypoxia and on the roles they play in the promotion of resistance to anti-cancer therapy.