Genetic and Functional Studies Implicate HIF1 α as a 14q Kidney Cancer Suppressor Gene
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Abstract
Kidney cancers often delete chromosome 3p, spanning the VHL tumor suppressor gene, and chromosome 14q, which presumably harbors ≥1 tumor suppressor genes. pVHL inhibits the hypoxia-inducible transcription factor (HIF), and HIF2α is a kidney cancer oncoprotein. In this article, we identify focal, homozygous deletions of the HIF1α locus on 14q in clear cell renal carcinoma cell lines. Wild-type HIF1α suppresses renal carcinoma growth, but the products of these altered loci do not. Conversely, downregulation of HIF1α in HIF1α-proficient lines promotes tumor growth. HIF1α activity is diminished in 14q-deleted kidney cancers, and all somatic HIF1α mutations identified in kidney cancers tested to date are loss of function. Therefore, HIF1α has the credentials of a kidney cancer suppressor gene. Significance: Deletion of 14q is a frequent event in clear cell renal carcinoma and portends a poor prognosis. In this study, we provide genetic and functional evidence that HIF1α is a target of 14q loss in kidney cancer. Cancer Discovery; 1(3); 222–35. © 2011 AACR. Read the Commentary on this article by Pal and Figlin, p. 198 This article is highlighted in the In This Issue feature, p. 189
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Those studies used 786-0 cells, which are pVHL-deficient RCC cells lacking HIF-1α, and may have adapted to depend selectively on HIF-2α.
“However, these studies were performed using 786–0 cells, which are pVHL deficient RCC cells that intrinsically lack HIF-1α expression, and may have thus adapted to selectively depend on HIF-2α [26–28].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [28]
The Results section ('Frequent Homozygous Deletions of the HIF1α Locus') identifies 786-O as a renal carcinoma line that lacks detectable wild-type HIF1α while producing HIF2α; it also reports an aberrant HIF1α protein, so 'lacking HIF-1α expression' needs that qualification. The Introduction describes HIF2α as a driver in pVHL-defective renal carcinomas, but the paper does not say that 786-O cells adapted to depend selectively on HIF2α, or establish that the cited studies all used 786-O cells. Page numbers were not available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe initial proposal that HIF-2α is pro-tumorigenic came from studies where HIF-2α overexpression, but not HIF-1α, blocked pVHL re-expression from inhibiting xenograft formation, and HIF-2α shRNA prevented xenograft formation.
“Specifically, the pro-tumorigenic role of HIF-2α was initially proposed based on studies showing that overexpression of HIF-2α, but not HIF-1α, abrogated the ability of pVHL re-expression to inhibit xenograft formation, and the converse that HIF-2α shRNA prevented tumor xenograft formation [26–28].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [28]
The Introduction (page unavailable) reports that HIF-2α, but not HIF-1α, can override pVHL’s tumor-suppressor activity and that eliminating HIF-2α suppresses tumor formation in preclinical models. It does not specify HIF-2α overexpression, pVHL re-expression, HIF-2α shRNA, or xenograft formation as the experiments behind those findings. (LLM, conf=0.84)
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Cowman, S. J., Fuja, D. G., Liu, X.-D., Tidwell, R. S. S., Kandula, N., Sirohi, D., Agarwal, A. M., Emerson, L. L., Tripp, S. R., Mohlman, J. S., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-3890 · Cited by 76 · see citing works
WSB1 promotes tumor metastasis by inducing pVHL degradation
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HIF regulates multiple translated endogenous retroviruses: Implications for cancer immunotherapy
Jiang, Q., Braun, D. A., Clauser, K. R., Ramesh, V., Shirole, N. H., Duke-Cohan, J. E., Nabilsi, N., Kramer, N. J., Forman, C., Lippincott, I. E., et al. (2025) · Cell · doi:10.1016/j.cell.2025.01.046 · Cited by 68 · see citing works
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The TGF-β/HDAC7 axis suppresses TCA cycle metabolism in renal cancer
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Regulation of the HIF switch in human endothelial and cancer cells
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HIF1α is not a target of 14q deletion in clear cell renal cancer
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- Authors
- Shen, C., Beroukhim, R., Schumacher, S. E., Zhou, J., Chang, M., Signoretti, S., & Kaelin, W. G.
- Affiliations
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- ORCID
- Venue
- Cancer Discovery
- Published
- 2011-08-01
- Volume
- 1
- Issue
- 3
- Pages
- 222-235
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC3202343
- OpenAlex
- W2159368804
- Cited by
- 413
- References
- 57
- Citations by year
- 2026: 15 · 2025: 17 · 2024: 28 · 2023: 28 · 2022: 28 · 2021: 37 · 2020: 31 · 2019: 31 · 2018: 34 · 2017: 28 · 2016: 25 · 2015: 33 · 2014: 27 · 2013: 23 · 2012: 23
- FWCI
- 8.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (R01CA068490)
- 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 › Chromatin Remodeling and Cancer
- Keywords
- HIF-1α, tumor suppressor, chromosome 14q deletion, clear cell renal cell carcinoma, hypoxia-inducible factor, VHL, HIF-2α, loss-of-function mutations, tumor growth inhibition, somatic mutations
- MeSH terms
- Animals, Carcinoma, Renal Cell, Chromosomes, Human, Pair 14, Humans, Kidney Neoplasms, Mice, Nude, Mutation, Genes, Tumor Suppressor, Cell Line, Tumor, Cell Proliferation, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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