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Review
. 2018 Sep 1;10(18):2227-2236.
doi: 10.4155/fmc-2018-0163. Epub 2018 Aug 9.

Hypoxia-inducible factor 2α: a novel target in gliomas

Jaclyn J Renfrow  1   2 , Michael H Soike  3 , Waldemar Debinski  4   2 , Shakti H Ramkissoon  5   6 , Ryan T Mott  5   2 , Mark B Frenkel  1 , Jann N Sarkaria  7 , Glenn J Lesser  2   8 , Roy E Strowd  2   8   9
Affiliations
Review

Hypoxia-inducible factor 2α: a novel target in gliomas

Jaclyn J Renfrow et al. Future Med Chem. .

Abstract

Hypoxia is an important contributor to aggressive behavior and resistance mechanisms in glioblastoma. Upregulation of hypoxia inducible transcription factors (HIFs) is the primary adaptive cellular response to a hypoxic environment. While HIF1α has been widely studied in cancer, HIF2α offers a potentially more specific and appealing target in glioblastoma given expression in glioma stem cells and not normal neural progenitors, activation in states of chronic hypoxia and expression that correlates with glioma patient survival. A first-in-class HIF2α inhibitor, PT2385, is in clinical trials for renal cell carcinoma, and provides the first opportunity to therapeutically target this important pathway in glioma biology.

Keywords: cancer; glioblastoma; hypoxia; hypoxia-inducible factors.

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Conflict of interest statement

Financial & competing interests disclosure

This work was supported by a Musella Foundation Grant (JJ Renfrow). Research reported in this publication was also supported by the National Cancer Institute's Cancer Center Support Grant award number P30CA012197 issued to the Wake Forest Baptist Comprehensive Cancer Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

<b>Figure 1.</b>
Figure 1.. In normoxia, cells degrade cytoplasmic hypoxia-inducible factor 2α after hydroxylation by prolyl hydroxylases 1–3 and polyubiquitination by Von Hippel-Lindau and E3 ubiquitin ligase.
Polyubiquitinated HIF2α undergoes proteasomal degradation. In hypoxia, PHD activity is reduced leading to cytoplasmic HIF2α stabilization, accumulation and translocation to the nucleus. In the nucleus, the α subunits dimerize with a complementary β subunit (HIF1β). This α/β active heterodimer binds to HREs within DNA promoter regions and drives gene expression contributing to cell proliferation, migration, metabolism, apoptosis, angiogenesis and survival. HRE: Hypoxic response element.
<b>Figure 2.</b>
Figure 2.. Immunohistochemistry for hypoxia-inducible factor 2α performed on formalin-fixed paraffin-embedded adult glioblastoma tissue demonstrates focal positive staining in the perivascular space.
This staining pattern suggests the possibility of a hypoxic gradient from dysfunctional vasculature leading to the focal upregulation of HIF2α.
See this image and copyright information in PMC

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