Cited by 116Cancer, Hypoxia, and MetabolismMechanisms of cancer metastasisCancer Cells and Metastasis

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Mouse Snail Is a Target Gene for HIF

Luo, Daochun, Wang, Jinxia, Li, Jeff, Post, Martin·2011·Molecular Cancer Research

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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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Authors: Luo, D., Wang, J., Li, J., & Post, M.
Affiliations: University of Toronto (CA)
ORCID: Post, Martin
Venue: Molecular Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2011-02-15
Volume: 9
Issue: 2
Pages: 234-245
ISSN: 1541-7786 (ISSN-L)
1557-3125
DOI: 10.1158/1541-7786.mcr-10-0214
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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Mouse Snail Is a Target Gene for HIF

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