Hypoxia-inducible factors: central regulators of the tumor phenotype

Abstract

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 alpha-subunit and a stable beta-subunit also referred to as ARNT. HIF-1alpha and HIF-2alpha 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.

Figure 1. HIF-1α and HIF-2α activate overlapping but distinct genes

HIF-1α and HIF-2α share the regulation of target genes involved in angiogenesis, invasion and metastasis, while HIF-1α alone activates genes involved in glycolysis and apoptosis. HIF-2α uniquely activates the stem cell factor Oct4 and Cyclin D1, while it preferentially regulates the growth factor TGFα. Abbreviations: Platelet derived growth factor (PDGF), fms- related tyrosine kinase 1 (Flt1), Tunica internal endothelial cell kinase 2 (Tie2), Plasminogen activator inhibitor 1 (PAI-1), Lactate dehydrogenase A (LDHA), BCL2/adenovirus E1B 19kDa interacting protein 3 (BNIP3), Cyclin D1 (CCD1).

Figure 2

Regulation of HIF-α stability: continuously transcribed and translated, the HIF-α subunits are degraded under normoxic conditions. Two prolines in the ODD are hydroxylated by PHD1, 2 or 3, allowing recognition by an E3 ubiquitin ligase complex including the VHL tumor suppressor protein. Following pVHL-mediated ubiquitylation, the HIF-α subunits are degraded in a proteasome-dependent fashion. When oxygen levels fall below ~5%, the PHDs are no longer active and the HIF-α subunits can translocate to the nucleus, where they bind co-factors including ARNT and p300 and transactivate hypoxia response genes, such as VEGF and PGK.