Hypoxia-Inducible Factor-1-Dependent Repression of E-cadherin in von Hippel-Lindau Tumor Suppressor–Null Renal Cell Carcinoma Mediated by TCF3, ZFHX1A, and ZFHX1B
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A critical event in the pathogenesis of invasive and metastatic cancer is E-cadherin loss of function. Renal clear cell carcinoma (RCC) is characterized by loss of function of the von Hippel-Lindau tumor suppressor (VHL), which negatively regulates hypoxia-inducible factor-1 (HIF-1). Loss of E-cadherin expression and decreased cell-cell adhesion in VHL-null RCC4 cells were corrected by enforced expression of VHL, a dominant-negative HIF-1α mutant, or a short hairpin RNA directed against HIF-1α. In human RCC biopsies, expression of E-cadherin and HIF-1α was mutually exclusive. The expression of mRNAs encoding TCF3, ZFHX1A, and ZFHX1B, which repress E-cadherin gene transcription, was increased in VHL-null RCC4 cells in a HIF-1–dependent manner. Thus, HIF-1 contributes to the epithelial-mesenchymal transition in VHL-null RCC by indirect repression of E-cadherin. (Cancer Res 2006; 66(5): 2725-31)
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Hypoxia and HIFs contribute to EMT by upregulating transcriptional repressors such as SNAIL, TWIST, TCF3, ZFHX1A, and ZFHX1B, whose gene products repress CDH1.
“Hypoxia and HIFs contribute to EMT by upregulating transcriptional repressors such as SNAIL (Imai et al., 2003), TWIST (Yang et al., 2008), TCF3, ZFHX1A, and ZFHX1B (Krishnamachary et al., 2006), whose gene products in turn repress CDH1.”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Krishnamachary et al., 2006
The RCC4-cell results and Figure 6 support HIF-1-dependent increases in TCF3, ZFHX1A, and ZFHX1B, which repress CDH1. But the same results section reports that hypoxia in VHL-restored RCC4 cells instead reduced these repressors' mRNAs and increased E-cadherin mRNA; the cited paper therefore does not support hypoxia-driven upregulation as a general claim. SNAIL and TWIST are cited to other papers in the sentence. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHypoxia or overexpression of HIF is sufficient to induce EMT and invasion in multiple cell types.
“Hypoxia or overexpression of HIF is sufficient to induce EMT and invasion in multiple cell types”
From Hypoxic control of metastasis (2016) · cites this paper as [70]
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- Authors
- Krishnamachary, B., Zagzag, D., Nagasawa, H., Rainey, K., Okuyama, H., Baek, J. H., & Semenza, G. L.
- Affiliations
- Johns Hopkins University (US)
- NYU Langone Health (US)
- Venue
- Cancer Research
- Published
- 2006-03-01
- Volume
- 66
- Issue
- 5
- Pages
- 2725-2731
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2045181115
- Cited by
- 415
- References
- 32
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 10 · 2023: 19 · 2022: 11 · 2021: 20 · 2020: 25 · 2019: 21 · 2018: 16 · 2017: 18 · 2016: 25 · 2015: 25 · 2014: 22 · 2013: 21 · 2012: 30
- FWCI
- 11.88
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Cancer Research (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- University of Pennsylvania
- Johns Hopkins University
- York University
- National Institutes of Health (CA103175)
- U.S. Public Health Service
- National Cancer Institute (P50CA103175)
- 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 › Mechanisms of cancer metastasis
- Keywords
- E-cadherin, HIF-1, von Hippel-Lindau tumor suppressor, clear cell renal cell carcinoma, HIF-1α, TCF3, ZEB2, epithelial-mesenchymal transition, transcriptional repression, cell-cell adhesion, metastasis
- MeSH terms
- Zinc Finger E-box-Binding Homeobox 1, Zinc Finger E-box Binding Homeobox 2, Biopsy, Carcinoma, Renal Cell, Cell Adhesion, Epithelial Cells, Humans, Immunohistochemistry, Kidney Neoplasms, Mesoderm, Repressor Proteins, RNA, Messenger, Transcription Factors, Transcription, Genetic, Down-Regulation, Cadherins, Gene Expression Regulation, Neoplastic, Homeodomain Proteins, RNA, Small Interfering, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, Von Hippel-Lindau Tumor Suppressor Protein
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