HIF-2α Enhances β-Catenin/TCF-Driven Transcription by Interacting with β-Catenin
Open accessAbstract
The tumor-promoting factors β-catenin and hypoxia-inducible factor (HIF) are often found to be coactivated in rapidly growing tumors. Recently, it was shown that HIF-1α negatively regulates Wnt/β-catenin signaling by sequestering β-catenin from β-catenin/T-cell factor (TCF). However, no investigation has been undertaken on the involvement of HIF-2α in β-catenin regulation. In this study, it was found that, like HIF-1α, HIF-2α interacts with β-catenin, but at a different site. Furthermore, HIF-2α was found to assemble with β-catenin/TCF and facilitate gene transcription. Mutational analyses revealed that transactivation domains of HIF-2α promote p300 coactivator recruitment by β-catenin. Furthermore, HIF-2α and β-catenin were found to associate in the nuclei of 786-0 renal cell carcinoma cells, and HIF-2α was found to be required for β-catenin activation in these cells and for their proliferation. These results suggest that this interaction contributes to the unrestrained growth of tumor cells containing coactivated HIF-2α and β-catenin. Interestingly, these actions of HIF-2α oppose those of HIF-1α on β-catenin and cell growth, and this suggests that HIF-1α/HIF-2α balance may importantly determine cell growth when hypoxia and Wnt stimulation coexist. Cancer Res; 70(24); 10101–11. ©2010 AACR.
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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 [14]
The Introduction (p. 1) and Discussion (pp. 9–10) describe HIF-2α as more growth-promoting than HIF-1α in ccRCC and link that difference to c-Myc and β-catenin signaling. The Results (p. 8) also report effects on cyclin D1. The passages do not establish the claimed comparative potency for TGF-α or VEGFA, so the full list of factors is not supported by this paper. (LLM, conf=0.88)
Experimental — accuracy not yet measuredBeyond canonical HRE-driven transcription, HIF isoforms differentially affect signaling pathways by interacting with non-PAS proteins such as p53, c-MYC, β-catenin, and the Notch intracellular domain.
“Apart from canonical HRE-mediated transcription, the HIF isoforms differentially modulate signaling pathways through interaction with proteins that do not contain PAS domains, such p53, the c-MYC proto-oncogene, β-catenin and the Notch intracellular domain (Fig. 2A) [11–15].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [14]
The Discussion (p. 9) describes HIF-1α interactions with p53, c-Myc, and β-catenin, and reports that HIF-1α and HIF-2α affect β-catenin signaling differently. Our copy does not address an interaction with the Notch intracellular domain or identify these partners as proteins without PAS domains. (LLM, conf=0.87)
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References 31 · Cited by 79
Research works printed but not linked: 1
- [2]2. Wang GL, Semenza GL. Purification and characterization of hypoxiainducible factor 1. J Biol Chem 1995;270:1230 -7.
- Authors
- Choi, H., Chun, Y.-S., Kim, T.-Y., & Park, J.-W.
- Affiliations
- Seoul National University (KR)
- Corresponding author
- Park, Jong-Wan
- Venue
- Cancer Research
- Published
- 2010-12-14
- Volume
- 70
- Issue
- 24
- Pages
- 10101-10111
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2154610459
- Semantic Scholar
- 67152debaae1558f696b5d72dd4f0bf85d8d543c
- Cited by
- 79
- References
- 31
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 5 · 2019: 4 · 2018: 3 · 2017: 5 · 2016: 9 · 2015: 12 · 2014: 4 · 2013: 7 · 2012: 14
- FWCI
- 2.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- HIF-2α, β-catenin, T-cell factor, Wnt/β-catenin signaling, transcriptional coactivation, p300 coactivator, protein-protein interaction, renal cell carcinoma, tumor cell proliferation, hypoxia, HIF-1α, cell growth
- MeSH terms
- Transcription Factor 4, Endothelial PAS Domain-Containing Protein 1, Carcinoma, Renal Cell, Humans, Kidney Neoplasms, Transcription Factors, Transcription, Genetic, Signal Transduction, Transcriptional Activation, Cell Hypoxia, Protein Structure, Tertiary, Cell Line, Tumor, Cell Growth Processes, E1A-Associated p300 Protein, beta Catenin, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Basic Helix-Loop-Helix Proteins, HEK293 Cells
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