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HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression
Open accessAbstract
Hypoxia-inducible factors (HIFs) are broadly expressed in human cancers, and HIF1α and HIF2α were previously suspected to promote tumour progression through largely overlapping functions. However, this relatively simple model has now been challenged in light of recent data from various approaches that reveal unique and sometimes opposing activities of these HIFα isoforms in both normal physiology and disease. These effects are mediated in part through the regulation of unique target genes, as well as through direct and indirect interactions with important oncoproteins and tumour suppressors, including MYC and p53. As HIF inhibitors are currently undergoing clinical evaluation as cancer therapeutics, a more thorough understanding of the unique roles performed by HIF1α and HIF2α in human neoplasia is warranted.
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“By recruiting transcriptional co-activators, HIFs regulate the expression of numerous genes involved in different processes including angiogenesis, metabolism, erythropoiesis, apoptosis, pH regulation, metastasis, and cellular differentiation (Semenza, 2003;Keith et al., 2012).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Keith et al., 2012
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“Deacetylation of HIF-2α by SIRT1, a deacetylase, increases HIF-2α's transcriptional activity, while deacetylation of HIF-1α results in transcriptional repression.”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Keith et al., 2012
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“Interestingly, the expression of VEGF, which is commonly considered a HIF-1α and HIF-2α target gene [19], was unchanged in all of the samples examined.”
From Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors (2014) · cites this paper as [19]
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“GLUT-1, known to be targeted by both HIF-1α and HIF-2α, was only decreased in 2 patients [19].”
From Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors (2014) · cites this paper as [19]
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1 retracted
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“11–13 Under normal O 2 availability, HIF α is constantly expressed and hydroxylated by PHDs on two conserved prolyl residues (Pro-405 and Pro-531 in HIF1 α ) present within an LXXLAP motif in its O 2 -dependent degradation domain.”
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“In addition, the deregulated expression of HIF transcription factors has been reported in several tumour types and thus far no effective therapies are known to target HIF-dependent effects (Keith et al., 2012).”
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“This illustration is in line with previous studies, in which Hif1 and Hif2, while sharing structural similarity and common target genes, have unique targets involved in different pathways (22, 23).”
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Background
Metadata
- Authors
- Keith, B., Johnson, R. S., & Simon, M. C.
- Affiliations
- Abramson Cancer Center (US)
- University of California San Diego (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Simon, M. Celeste
- Venue
- Nature Reviews Cancer
- Published
- 2011-12-15
- Volume
- 12
- Issue
- 1
- Pages
- 9-22
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- PMC
- PMC3401912
- OpenAlex
- W1998664010
- Cited by
- 1,693
- References
- 197
- Citations by year
- 2026: 82 · 2025: 82 · 2024: 112 · 2023: 116 · 2022: 126 · 2021: 135 · 2020: 118 · 2019: 124 · 2018: 123 · 2017: 117 · 2016: 112 · 2015: 112 · 2014: 141 · 2013: 122 · 2012: 70
- FWCI
- 7.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature reviews. Cancer (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- Wellcome Trust (092738/Z/10/Z)
- National Heart, Lung, and Blood Institute (R01HL066310)
- National Cancer Institute (R01CA158301)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Kruppel-like factors research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- HIF-1α, HIF-2α, hypoxia-inducible factor, tumor hypoxia, tumor progression, HIF target genes, c-Myc, p53, HIF inhibitors, cancer therapeutics, oxygen sensing
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Endothelial PAS Domain-Containing Protein 1, Acetylation, Animals, Gene Expression Regulation, Humans, Neoplasms, Protein Processing, Post-Translational, Proteins, Cell Hypoxia, Genes, p53, Genes, myc, Disease Progression, Multiprotein Complexes, Cell Proliferation, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, TOR Serine-Threonine Kinases
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