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Untuning the tumor metabolic machine: HIF-α: pro- and antitumorigenic?

Nature Medicine volume 18, pages 1024–1025 (2012)Cite this article

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Solid tumors contain regions of oxygen (O2) and nutrient limitation resulting from their structurally and functionally abnormal vasculature and the rapid proliferation of cancer cells. The major transcriptional response to hypoxia is mediated by hypoxia-inducible factors (HIFs), which stimulate the expression of hundreds of genes that promote cellular adaptation to low O2. Some of the HIF target genes regulate processes involved in tumorigenesis, such as increased glucose uptake and glycolysis, angiogenesis, invasion, metastasis and radiation resistance. Furthermore, a number of common oncogenic drivers, such as mTORC1 and Ras, enhance HIF activity.

HIFs function as heterodimers, composed of stable β-subunits and O2-sensitive α-subunits, which accumulate upon O2 deprivation. In normal O2 conditions, HIF-αs are modified by metabolically regulated prolyl hydroxylases (PHDs), leading to physical interactions between HIF-α subunits and the von Hippel-Lindau (VHL)-associated E3 ubiquitin ligase, resulting in rapid HIF-α turnover. Two well-characterized isoforms of the α-subunit, HIF-1α and HIF-2α, have both overlapping functions as well as divergent and even antagonistic roles in hypoxic responses1. High HIF-1α and HIF-2α protein amounts in diagnostic tumor biopsies are correlated with poor prognosis in cancers of the bladder, brain, breast, colon, cervix, endometrium, head and neck, lung, ovary, pancreas, prostrate, rectum and stomach2. These studies strongly support the development of pharmacological HIF inhibitors for cancer treatment.

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Figure 1: A model for how 2HG promotes glioma transformation.

Kaite Vicari

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Authors and Affiliations

  1. Regina M Young and M Celeste Simon are at the Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.,

    Regina M Young & M Celeste Simon

  2. Regina M Young is also in the Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.,

    Regina M Young

  3. M Celeste Simon is also at the Howard Hughes Medical Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.,

    M Celeste Simon

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  1. Regina M Young
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  2. M Celeste Simon
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Correspondence to M Celeste Simon.

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Young, R., Simon, M. Untuning the tumor metabolic machine: HIF-α: pro- and antitumorigenic?. Nat Med 18, 1024–1025 (2012). https://doi.org/10.1038/nm.2865

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