Hypoxia inducible factor-2α: 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-1α and HIF-2α, which activate the expression of genes involved in proliferation, metabolism, angiogenesis, and metastasis. While highly homologous, HIF-1α and HIF-2α have been shown to have different roles in tumorigenesis dependent on specific tumor microenvironments. Here we summarize recent studies on HIF-2α and discuss the potential mechanisms whereby it contributes to tumor aggressiveness.

Human cancers converge at the HIF-2α oncogenic axis

“…We show that genetically diverse human cancers have evolved a common and obligatory growth stimulatory program, required for tumor formation, at the hub of which lies HIF-2␣. Consistently, HIF-2␣ stabilization is observed in the vast majority of solid tumors, as a consequence of both mutational events and environmental cues, and is associated with aggressive tumorigenic behaviors (17,18,38). Our data further suggest that HIF-2␣ endows cells with the ability to proliferate autonomously by activating fundamental RTKs, including EGFR and IGF1R, and their downstream signaling pathways.…”

DNMT3a epigenetic program regulates the HIF-2α oxygen-sensing pathway and the cellular response to hypoxia

“…Silencing of HIF-2α suppresses tumorigenesis of various genetically diverse cancers, further highlighting its central role in malignancy (16,17,20,21), although this depends on the experimental context (22). Therefore, EPAS1 is silent in adult epithelia but undergoes unscheduled activation in several malignancies, driving proliferation in the hypoxic tumor microenvironment (23).…”

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

“…Interestingly, peroxisome abundance is reduced more frequently in well-differentiated tumors, however, it remains to be determined if induction of pexophagy and subsequent loss of peroxisomes promotes or slows down tumor growth. Since HIF-2α stabilization is observed in the vast majority of solid tumors (Franovic et al, 2009;Qing and Simon, 2009), we propose that in addition to ccRCC HIF-2α-mediated pexophagy might also lead to reduced peroxisome abundance in other cancer types.…”