HIF-1α Promotes Epithelial-Mesenchymal Transition and Metastasis through Direct Regulation of ZEB1 in Colorectal Cancer
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It is well recognized that hypoxia-inducible factor 1 alpha (HIF-1α) is involved in cancer metastasis, chemotherapy and poor prognosis. We previously found that deferoxamine, a hypoxia-mimetic agent, induces epithelial-mesenchymal transition (EMT) in colorectal cancer. Therefore, here we explored a new molecular mechanism for HIF-1α contributing to EMT and cancer metastasis through binding to ZEB1. In this study, we showed that overexpression of HIF-1α with adenovirus infection promoted EMT, cell invasion and migration in vitro and in vivo. On a molecular level, HIF-1α directly binding to the proximal promoter of ZEB1 via hypoxia response element (HRE) sites thus increasing the transactivity and expression of ZEB1. In addition, inhibition of ZEB1 was able to abrogate the HIF-1α-induced EMT and cell invasion. HIF-1α expression was highly correlated with the expression of ZEB1 in normal colorectal epithelium, primary and metastatic CRC tissues. Interestingly, both HIF-1α and ZEB1 were positively associated with Vimentin, an important mesenchymal marker of EMT, whereas negatively associated with E-cadherin expression. These findings suggest that HIF-1α enhances EMT and cancer metastasis by binding to ZEB1 promoter in CRC. HIF-1α and ZEB1 are both widely considered as tumor-initiating factors, but our results demonstrate that ZEB1 is a direct downstream of HIF-1α, suggesting a novel molecular mechanism for HIF-1α-inducing EMT and cancer metastasis.
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HIF has a direct regulatory effect on EMT-related proteins, such as ZEB1, Snail, and Twist.
“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 [87]
HIF directly regulates key EMT transcription factors ZEB1, Snail, and Twist through functional hypoxia response elements within the regulatory elements of these genes.
“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 [73]
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- Authors
- Zhang, W., Shi, X., Peng, Y., Wu, M., Zhang, P., Xie, R., Wu, Y., Yan, Q., Liu, S., & Wang, J.
- Affiliations
- Kunming University of Science and Technology (CN)
- Nanfang Hospital (CN)
- Corresponding author
- Liu, Side
- Wang, Jide
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-06-09
- Volume
- 10
- Issue
- 6
- Pages
- e0129603
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4461314
- OpenAlex
- W621464006
- Cited by
- 261
- References
- 33
- Citations by year
- 2026: 13 · 2025: 11 · 2024: 14 · 2023: 25 · 2022: 28 · 2021: 28 · 2020: 35 · 2019: 24 · 2018: 34 · 2017: 26 · 2016: 18 · 2015: 5
- FWCI
- 9.14
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China
- Southern Medical University
- Nanfang Hospital (G201227)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- HIF-1α, ZEB1, epithelial-mesenchymal transition, colorectal cancer, metastasis, hypoxia response element, transcriptional regulation, cell invasion, cell migration, vimentin, E-cadherin, deferoxamine, tumor suppressor
- MeSH terms
- Zinc Finger E-box-Binding Homeobox 1, Animals, Base Sequence, Humans, Liver Neoplasms, Mice, Nude, Molecular Sequence Data, Transcription Factors, Vimentin, Colorectal Neoplasms, Cadherins, Gene Expression Regulation, Neoplastic, Homeodomain Proteins, HT29 Cells, Response Elements, HCT116 Cells, Hypoxia-Inducible Factor 1, alpha Subunit, Epithelial-Mesenchymal Transition
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