Hypoxia inducible factor-2alpha: a critical mediator of aggressive tumor phenotypes

Abstract

Intra-tumoral hypoxia (low oxygen [O(2)] level) is an independent indicator of unfavorable patient diagnosis, and increasing evidence demonstrates that hypoxia contributes to a more aggressive tumor phenotype. Adaptation to hypoxia is predominantly regulated by two structurally related hypoxia inducible factors, HIF-1alpha and HIF-2alpha, which activate the expression of genes involved in proliferation, metabolism, angiogenesis, and metastasis. While highly homologous, HIF-1alpha and HIF-2alpha have been shown to have different roles in tumorigenesis dependent on specific tumor microenvironments. Here we summarize recent studies on HIF-2alpha and discuss the potential mechanisms whereby it contributes to tumor aggressiveness.

Figure 1. Regulation of HIF-2α expression

A, Under normoxia, HIF-2α is hydroxylated by PHDs at proline 406 and 531. Hydroxylation leads to pVHL binding and subsequent degradation of HIF-2α by the 26S proteasome. B, Under hypoxia, when iron levels are adequate, HIF-2α is stabilized due to inhibition of PHD activities and forms complexes with ARNT to transactivate expression of hypoxia inducible genes. C, Under hypoxia, when iron is deficient, IRPs bind to the IRE within 5′UTR of HIF-2α mRNA, which in turn inhibits the translation of HIF-2α. See text for details. IRE: iron response element; IRP: IRE binding pritein; PHD: prolyl hydroxylase-domain protein; FIH: factor inhibiting HIF.

Figure 2. Mechanisms whereby HIF-2α contributes to an aggressive tumor phenotype

A, HIF-2α activates expression of genes involved in proliferation, angiogenesis, metastasis, and differentiation. Regulation of TWIST by HIF-2α seems to be controversal. B, HIF-2α selectively activates expression of unknown gene X, which may enhance binding of polysomes to EGFR mRNA and subsequently its translation efficiency. C, HIF-2α enhances c-Myc activities by stabilizing c-Myc-Max complexes, increasing expression of c-Myc targets involved in cell cycle progression. See text for details.