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 expression of numerous genes involved in angiogenesis, metabolism, erythropoiesis, apoptosis, pH regulation, metastasis, and cellular differentiation.
“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
The Introduction and ‘Direct regulation of gene expression by HIF1α and HIF2α’ (pages unavailable) say that HIFs regulate many hypoxia-induced genes and discuss targets involved in processes such as metabolism and differentiation. But the review describes interactions with transcriptional co-factors as likely, rather than establishing co-activator recruitment as the mechanism for the entire listed range; the passages examined do not establish pH regulation as part of that range. (LLM, conf=0.82)
Experimental — accuracy not yet measuredDeacetylation of HIF-2α by SIRT1 increases HIF-2α's transcriptional activity, while deacetylation of HIF-1α results in transcriptional repression.
“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
The Acetylation section states that SIRT1 deacetylation enhances HIF-2α transcriptional activity. It also reports HIF-1α transcriptional repression, but says that effect was not universally observed; the claim omits that qualification. No page number is provided in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredVEGF expression was unchanged in all samples examined.
“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]
GLUT-1 was decreased in two patients.
“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]
The passages from the review’s Acetylation and Differential stability sections discuss HIF activity and glucose transport, but do not report GLUT-1 decreasing in two patients. Searches for “GLUT-1,” “GLUT1,” and “two patients decreased expression” found no passage addressing that patient-level result. (LLM, conf=0.75)
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Self-citationKidney Cancer: Now Available in a New Flavor
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Targeting Hypoxia-Inducible Factors for the Treatment of Anemia in Chronic Kidney Disease Patients
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“BPTES inhibition of hGA(124-551), a truncated form of human kidneytype glutaminase.”
Iron and cancer: more ore to be mined
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“…a protumorigenic and immunosuppressive phenotype (Casazza et al., 2014; Colegio et al., 2014; Finger and Giaccia, 2010; Hanahan and Coussens, 2012; Keith et al., 2012; Motz and Coukos, 2013; Noy and Pollard, 2014; Cancer Cell 26, November 10, 2014 ª2014 Elsevier Inc. 605 NS, not significant;…”
Hypoxia and the extracellular matrix: drivers of tumour metastasis
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Normalizing Tumor Microenvironment to Treat Cancer: Bench to Bedside to Biomarkers
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Self-citationHIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations
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HIF transcription factors, inflammation, and immunity
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“As has been shown in cancer cells (Holmquist-Mengelbier et al., 2006; Keith et al., 2012; Warnecke et al., 2008), differing expression patterns of the HIF-1a and HIF-2a isoforms in immune cells depend on both intrinsic and extrinsic factors, and their resulting balance specifically contributes to…”
BackgroundSelf-citationAnoikis molecular pathways and its role in cancer progression
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Links between metabolism and cancerPreprint
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“Several of the enzymes elevated in AMPKa-deficient cells are known targets of the transcription factor HIF-1a, one of the central regulators of glycolysis induced by hypoxia (Keith et al., 2012; Semenza, 2011).”
BackgroundVHL, the story of a tumour suppressor gene
Gossage, L., Eisen, T. G., & Maher, E. R. (2014) · Nature reviews. Cancer · doi:10.1038/nrc3844 · Cited by 777 · see citing works
Targeting renal cell carcinoma with a HIF-2 antagonist
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“A comprehensive description of HIF-α regulation and the conflicting roles of HIF-1α and HIF-2α are given in Keith et al. (2012).”
BackgroundInfluentialRegulation of mTORC1 and its impact on gene expression at a glance
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“The increase in HIF1a activity, which results from oncogenic activation and/or intratumoral hypoxia, has been associated with an increased patient mortality in several types of cancer (reviewed by Keith et al., 2012).”
BackgroundThe histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism
Sebastián, C., Zwaans, B. M. M., Silberman, D. M., Gymrek, M., Goren, A., Zhong, L., Ram, O., Truelove, J., Guimaraes, A. R., Toiber, D., et al. (2012) · Cell · doi:10.1016/j.cell.2012.10.047 · Cited by 660 · see citing works
“Moreover, HIF-1 α and HIF-2 α have overlapping functions, and how these two factors influence tumorigenesis remains still highly controversial (Keith et al., 2012).”
Monocarboxylate transporters in cancer
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Clear cell renal cell carcinoma ontogeny and mechanisms of lethality
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How the Warburg effect supports aggressiveness and drug resistance of cancer cells?
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Passing the baton: the HIF switch
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Self-citationGlycolytic Reprogramming in Myofibroblast Differentiation and Lung Fibrosis
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HIF ‐1 at the crossroads of hypoxia, inflammation, and cancer
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PDK1-Dependent Metabolic Reprogramming Dictates Metastatic Potential in Breast Cancer
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“HIF-1a Mediates Metabolic Reprogramming of Liver-Metastatic Breast Cancer Cells HIF-1a is a master transcription factor that controls metabolic reprogramming under low-O2 conditions, and it functions as a key regulator of glycolysis (Keith et al., 2012; Semenza, 2013).”
Tumor Microenvironment Complexity: Emerging Roles in Cancer Therapy
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ROS production by mitochondria: function or dysfunction?
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Hypoxia-Modified Cancer Cell Metabolism
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Mitochondrial Dysfunction in Cancer
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Tumor Microenvironment in Pancreatic Cancer Pathogenesis and Therapeutic Resistance
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“HIF-1α and HIF-2α have different expression profiles and different targets.”
BackgroundInfluentialOxygen availability and metabolic adaptations
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Self-citationPersonalized Management of Pheochromocytoma and Paraganglioma
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“Through HIF-α stabilization, cluster 1 mutations promote angiogenesis (eg, vascular endothelial growth factor (VEGF)/PDGF transcription), tumor extravasation, migration, invasion, metastasis, and other cellular processes (49-51).”
BackgroundMetabolic control of epigenetics in cancer
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Hypoxia, Hypoxia-inducible Transcription Factors, and Renal Cancer
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Somatic<i>HIF2A</i>Gain-of-Function Mutations in Paraganglioma with Polycythemia
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Self-citationThe VHL/HIF axis in clear cell renal carcinoma
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“THE IRE/IRP SYSTEM IN CANCER Considering that HIF2α may function either as a tumor promoter or suppressor (Keith et al., 2012), the regulation of HIF2α mRNA translation by IRP1 provides a link between the IRE/IRP system and cancer biology.”
BackgroundRedox control of inflammation in macrophages
Brüne, B., Dehne, N., Grossmann, N., Jung, M., Namgaladze, D., Schmid, T., von Knethen, A., & Weigert, A. (2013) · Antioxidants & Redox Signaling · doi:10.1089/ars.2012.4785 · Cited by 377 · see citing works
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Structural integration in hypoxia-inducible factors
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Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases
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Vascular Permeability and Drug Delivery in Cancers
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“For example, HIF-1a promotes cell cycle arrest, whereas HIF-2a promotes progression through the cell cycle, likely in a cell context-dependent manner (Keith et al. 2012).”
BackgroundA Small-Molecule Antagonist of HIF2α Is Efficacious in Preclinical Models of Renal Cell Carcinoma
Wallace, E. M., Rizzi, J. P., Han, G., Wehn, P. M., Cao, Z., Du, X., Cheng, T., Czerwinski, R. M., Dixon, D. D., Goggin, B. S., et al. (2016) · Cancer Research · doi:10.1158/0008-5472.can-16-0473 · Cited by 336 · see citing works
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The Role of Hypoxia in Glioblastoma Invasion
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“HIFs are heterodimeric complexes constituted by O2-regulated α subunits (HIF-1α, EPAS1/HIF-2α, or HIF-3α) and a constitutively expressed β subunit, HIF-1β, also known as an aryl hydrocarbon receptor nuclear translocator (ARNT) [34,35].”
BackgroundGameiro, P. A., Yang, J., Metelo, A. M., Pérez-Carro, R., Baker, R., Wang, Z., Arreola, A., Rathmell, W. K., Olumi, A., López-Larrubia, P., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.02.002 · Cited by 325 · see citing works
Allosteric inhibition of hypoxia inducible factor-2 with small molecules
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Anaemia in kidney disease: harnessing hypoxia responses for therapy
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CAR-T Cells Hit the Tumor Microenvironment: Strategies to Overcome Tumor Escape
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“This family of transcription factors is mainly comprised of two isoforms: HIF-1α and HIF-2α (107), with HIF-1α being the main isoform expressed by activated T cells (108).”
BackgroundMechanisms of hypoxia signalling: new implications for nephrology
Schödel, J., & Ratcliffe, P. J. (2019) · Nature Reviews Nephrology · doi:10.1038/s41581-019-0182-z · Cited by 309 · see citing works
Oxygen sensing and hypoxia signalling pathways in animals: The implications of physiology for cancer
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“Interestingly, in support of an antitumourigenic action of HIF-1α in this context, human VHL-defective CCRC is associated with a high prevalence of copy number reduction for a region of chromosome 14q containing HIF-1α, amongst other genes (Shen et al. 2011).”
BackgroundInfluentialHypoxia-driven pathways in bone development, regeneration and disease
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Hypoxia-Induced Epithelial-Mesenchymal Transition in Cancers: HIF-1α and Beyond
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miRNAs regulate the HIF switch during hypoxia: a novel therapeutic target
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SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer
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The EGLN-HIF O 2 -Sensing System: Multiple Inputs and Feedbacks
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PHENOTYPIC PLASTICITY AND EPIGENETIC MARKING: AN ASSESSMENT OF EVIDENCE FOR GENETIC ACCOMMODATION
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“These responses to hypoxia are mediated by the hypoxia-inducible factor (HIF) signaling cascade, which affects expression of genes involved in erythrocyte production, glycolysis, pH homeostasis, lipid metabolism, and the formation of new blood vessels (Chen et al. 2012a; Keith et al. 2012).”
BackgroundTargeting the Tumor Microenvironment: From Understanding Pathways to Effective Clinical Trials
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“Hypoxia, a critical feature in the tumor microenvironment, has been shown to promote cancer stemness through the hypoxiainducible factors (HIFs) (15, 16).”
BackgroundLoss of the Tumor Suppressor LKB1 Promotes Metabolic Reprogramming of Cancer Cells via HIF-1α
Faubert, B., Vincent, E. E., Griss, T., Samborska, B., Izreig, S., Svensson, R. U., Mamer, O. A., Avizonis, D., Shackelford, D. B., Shaw, R. J., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1312570111 · Cited by 278 · see citing works
Oxidative stress and metal carcinogenesis
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Collagen prolyl 4-hydroxylase 1 is essential for HIF-1α stabilization and TNBC chemoresistance
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“In vitro experiments show that HIF-1α and HIF-2α inhibit insulin signaling in both human and murine white adipocytes [120].”
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“It is clear that the rapid growth of solid tumors contributes to the hypoxic environment and elevates the expression of HIFs.(1,24) In accordance, the HIF-1α level gradually increased during tumor growth in an orthotopic liver tumor model (Fig.”
BackgroundDirect regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET
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The Mitochondrial Chaperone TRAP1 Promotes Neoplastic Growth by Inhibiting Succinate Dehydrogenase
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“regulators of genes encoding glycolytic enzymes, glucose transporters, and also mediators of angiogenesis and tumour metastasis [53].”
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Oxygen Sensing by T Cells Establishes an Immunologically Tolerant Metastatic Niche
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Paracrine Induction of HIF by Glutamate in Breast Cancer: EglN1 Senses Cysteine
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“Levels of HIF-1a are generally increased in aggressive tumors (Keith et al., 2012) and could be useful as a molecular predictor of poor prognosis and treatment response in HCC (Xiang et al., 2011; Nath and Szabo, 2012; Zheng et al., 2013).”
Background
- 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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