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Mouse Snail Is a Target Gene for HIF
Abstract
The transcriptional inhibitor Snail is a critical regulator for epithelial–mesenchymal transition (EMT). Although low oxygen induces Snail transcription, thereby stimulating EMT, a direct role of hypoxia-inducible factor (HIF) in this process remains to be demonstrated. Here we show that hypoxia induces the expression of Snail via HIF. In silico analysis identified a potential hypoxia-response element (HRE) close to the minimal promoter of the human and mouse genome of the snail gene. Gel shift assays demonstrated that a specific hypoxia-inducible complex is formed with the putative HRE and that the complex contains HIF proteins. ChIP assays confirmed the interaction of HIF proteins with the putative HRE in vivo. Reporter gene analyses showed that the putative HRE responds to hypoxia in its natural position as well as in front of a heterologous promoter and that the HRE is directly activated by HIF-1α or HIF-2α. HIF knockdown with siRNA at 2% oxygen and overexpression of an oxygen-insensitive HIF (HIF-ΔODD) mutant at 21% oxygen showed that HIF regulates Snail activation and subsequent cell migration. Our findings identify snail as a HIF target gene and provide novel insights into the regulation of snail and hypoxia-induced EMT. Mol Cancer Res; 9(2); 234–45. ©2011 AACR.
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“Studies have demonstrated that HIF has a direct regulatory effect on EMT‐related proteins, such as zinc finger E‐box binding homeobox 1, Snail and Twist.”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [86]
In the citing paper
“A direct role for HIF in the regulation of key EMT transcription factors such as ZEB1, Snail, and Twist has been demonstrated through the identification of functional hypoxia response elements (HREs) within the regulatory elements of these genes”
From Hypoxic control of metastasis (2016) · cites this paper as [72]
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Research works printed but not linked: 1
- Bachelder, 2005, Glycogen synthase kinase-3 is an endogenous inhibitor of Snail transcription: implications for the epithelial-mesenchymal transition, J Cell Biol, 168, 29, 10.1083/jcb.200409067 · DOI
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Metadata
- Authors
- Luo, D., Wang, J., Li, J., & Post, M.
- Affiliations
- University of Toronto (CA)
- ORCID
- Post, Martin
- Venue
- Molecular Cancer Research
- Published
- 2011-02-15
- Volume
- 9
- Issue
- 2
- Pages
- 234-245
- ISSN
- 1541-7786 (ISSN-L)
- 1557-3125
- OpenAlex
- W2141808185
- Cited by
- 116
- References
- 52
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 7 · 2022: 4 · 2021: 7 · 2020: 8 · 2019: 7 · 2018: 12 · 2017: 8 · 2016: 9 · 2015: 14 · 2014: 7 · 2013: 10 · 2012: 8
- FWCI
- 3.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (MOP-77751)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- snails, hypoxia-inducible factor, HIF-1α, HIF-2α, hypoxia, epithelial-mesenchymal transition, hypoxia response element, transcriptional regulation, cell migration
- MeSH terms
- Snail Family Transcription Factors, Endothelial PAS Domain-Containing Protein 1, Animals, Base Sequence, Cell Movement, Gene Expression Regulation, Humans, Molecular Sequence Data, Protein Binding, RNA, Messenger, Transcription Factors, Cell Hypoxia, Response Elements, Electrophoretic Mobility Shift Assay, Endothelial Cells, Chromatin Immunoprecipitation, Mice, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Epithelial-Mesenchymal Transition
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