Targeting HIF-2α in the Tumor Microenvironment: Redefining the Role of HIF-2α for Solid Cancer Therapy

SIMPLE SUMMARY: Hypoxia is defined as the inadequate supply of oxygen in tissues. Regions of acute and chronic hypoxia are a universal feature of the tumor microenvironment and a known driver of tumor progression and therapeutic resistance. As oxygen levels decrease, transcription factor HIF-1α and HIF-2α stabilize and positively regulate the hypoxic response, modulating many of the cell’s defining functions. As a result, HIF-α activation in response to tumor hypoxia can drive tumor progression, making HIF-1α and HIF-2α the primary targets for therapeutic intervention. However, although HIF-α can both sequentially and differentially regulate the hypoxic response, the role of HIF-2α is vastly under-considered. In this review, we discuss the role of HIF-2α in physiology and tumor progression and the differences between HIF-1α and HIF-2α in structure, function, and regulation of the hypoxic response. Notably, we conclude that cancer therapeutics which target HIF-2α have the potential to supplement current solid tumor fighting strategies. ABSTRACT: Inadequate oxygen supply, or hypoxia, is characteristic of the tumor microenvironment and correlates with poor prognosis and therapeutic resistance. Hypoxia leads to the activation of the hypoxia-inducible factor (HIF) signaling pathway and stabilization of the HIF-α subunit, driving tumor progression. The homologous alpha subunits, HIF-1α and HIF-2α, are responsible for mediating the transcription of a multitude of critical proteins that control proliferation, angiogenic signaling, metastasis, and other oncogenic factors, both differentially and sequentially regulating the hypoxic response. Post-translational modifications of HIF play a central role in its behavior as a mediator of transcription, as well as the temporal transition from HIF-1α to HIF-2α that occurs in response to chronic hypoxia. While it is evident that HIF-α is highly dynamic, HIF-2α remains vastly under-considered. HIF-2α can intensify the behaviors of the most aggressive tumors by adapting the cell to oxidative stress, thereby promoting metastasis, tissue remodeling, angiogenesis, and upregulating cancer stem cell factors. The structure, function, hypoxic response, spatiotemporal dynamics, and roles in the progression and persistence of cancer of this HIF-2α molecule and its EPAS1 gene are highlighted in this review, alongside a discussion of current therapeutics and future directions.