Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma
Open accessAbstract
Defective function of the von Hippel-Lindau (VHL) tumor suppressor ablates proteolytic regulation of hypoxia-inducible factor alpha subunits (HIF-1alpha and HIF-2alpha), leading to constitutive activation of hypoxia pathways in renal cell carcinoma (RCC). Here we report a comparative analysis of the functions of HIF-1alpha and HIF-2alpha in RCC and non-RCC cells. We demonstrate common patterns of HIF-alpha isoform transcriptional selectivity in VHL-defective RCC that show consistent and striking differences from patterns in other cell types. We also show that HIF-alpha isoforms display unexpected suppressive interactions in RCC cells, with enhanced expression of HIF-2alpha suppressing HIF-1alpha and vice-versa. In VHL-defective RCC cells, we demonstrate that the protumorigenic genes encoding cyclin D1, transforming growth factor alpha, and vascular endothelial growth factor respond specifically to HIF-2alpha and that the proapoptotic gene encoding BNip3 responds positively to HIF-1alpha and negatively to HIF-2alpha, indicating that HIF-1alpha and HIF-2alpha have contrasting properties in the biology of RCC. In keeping with this, HIF-alpha isoform-specific transcriptional selectivity was matched by differential effects on the growth of RCC as tumor xenografts, with HIF-1alpha retarding and HIF-2alpha enhancing tumor growth. These findings indicate that therapeutic approaches to targeting of the HIF system, at least in this setting, will need to take account of HIF isoform-specific functions.
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The HIF-2α bias in ccRCC is attributed to HIF-2α being more potent than HIF-1α at inducing pro-tumorigenic factors such as Cyclin D1, TGF-α, VEGFA, c-Myc, and β-catenin.
“The HIF-2α bias observed in ccRCC has been attributed to the increased potency of HIF-2α compared to HIF-1α in promoting pro-tumorigenic factors such as Cyclin D1, TGF-α, VEGFA, c-Myc and β-catenin [14,18–20].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [18]
The Discussion (p. 5683) reports that HIF-2α, unlike HIF-1α, positively regulates cyclin D1, TGF-α and VEGF in VHL-defective renal carcinoma cells. It does not establish HIF-2α promotion of c-Myc or β-catenin, and the Discussion says the authors could not determine what drives the observed HIF-2α bias. (LLM, conf=0.87)
Experimental — accuracy not yet measuredEarly studies showed that HIF-1 (but not HIF-2) induced expression of several glycolytic genes in various cell types, while unique HIF-2 target genes seemed to be cell type specific.
“Early studies showed that HIF-1 (but not HIF-2) induced expression of several glycolytic genes in various cell types, while unique HIF-2 target genes seemed to be cell type specific (Hu et al., 2003;Raval et al., 2005).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Raval et al., 2005
HIF transcriptional target specificity was strikingly different in VHL-defective RCC cells compared to other cell types, and the HIF isoforms also showed a mutually dependent suppressive function in RCC.
“HIF transcriptional target specificity was strikingly different in VHL-defective RCC cells compared to other cell types, and the HIF isoforms also showed a mutually dependent suppressive function in RCC (Raval et al., 2005).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Raval et al., 2005
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- Authors
- Raval, R. R., Lau, K. W., Tran, M. G. B., Sowter, H. M., Mandriota, S. J., Li, J.-L., Pugh, C. W., Maxwell, P. H., Harris, A. L., & Ratcliffe, P. J.
- Affiliations
- University of Oxford (GB)
- Hammersmith Hospital (GB)
- Cancer Research UK (GB)
- Corresponding author
- Ratcliffe, Peter J.
- ORCID
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2005-07-01
- Volume
- 25
- Issue
- 13
- Pages
- 5675-5686
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC1157001
- OpenAlex
- W1990607537
- Semantic Scholar
- ea22eef976a8498d9b440e9cf543425e3baaa66d
- Cited by
- 940
- References
- 52
- Citations by year
- 2026: 13 · 2025: 24 · 2024: 30 · 2023: 38 · 2022: 36 · 2021: 38 · 2020: 43 · 2019: 40 · 2018: 33 · 2017: 37 · 2016: 50 · 2015: 58 · 2014: 48 · 2013: 63 · 2012: 55
- FWCI
- 20.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- PEARL (University of Plymouth) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust
- Cancer Research UK
- Agency for Science, Technology and Research
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- HIF-1, HIF-2, von Hippel-Lindau tumor suppressor, renal cell carcinoma, transcriptional regulation, HIF-1α, HIF-2α, cyclin D1, transforming growth factor-alpha, vascular endothelial growth factor, BNIP3, apoptosis, tumor growth, xenografts
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Amino Acid Sequence, Animals, Carcinoma, Renal Cell, DNA-Binding Proteins, von Hippel-Lindau Disease, Humans, Immunohistochemistry, Kidney Neoplasms, Mice, Nude, Mutation, Neoplasm Transplantation, Nuclear Proteins, Retroviridae, Transcription Factors, Transplantation, Heterologous, Genes, Tumor Suppressor, Transforming Growth Factor alpha, Cyclins, Protein Structure, Tertiary, RNA, Small Interfering, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Cyclin D
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