Hypoxia-inducible factors: central regulators of the tumor phenotype

Low oxygen levels are a defining characteristic of solid tumors, and responses to hypoxia contribute substantially to the malignant phenotype. Hypoxia-induced gene transcription promotes characteristic tumor behaviors, including angiogenesis, invasion, metastasis, de-differentiation and enhanced glycolytic metabolism. These effects are mediated, at least in part, by targets of the hypoxia-inducible factors (HIFs). The HIFs function as heterodimers comprising an oxygen-labile α-subunit and a stable β-subunit also referred to as ARNT. HIF-1α and HIF-2α stimulate the expression of overlapping as well as unique transcriptional targets, and their induction can have distinct biological effects. New targets and novel mechanisms of dysregulation place the HIFs in an ever more central role in tumor biology and have led to development of pharmacological inhibitors of their activity.