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The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion
J Comijn1, G Berx, P Vermassen
1Molecular Cell Biology Unit, Department of Molecular Biology, VIB-Ghent University, B-9000, Ghent, Belgium.
Abstract:
Transcriptional downregulation of E-cadherin appears to be an important event in the progression of various epithelial tumors. SIP1 (ZEB-2) is a Smad-interacting, multi-zinc finger protein that shows specific DNA binding activity. Here, we report that expression of wild-type but not of mutated SIP1 downregulates mammalian E-cadherin transcription via binding to both conserved E2 boxes of the minimal E-cadherin promoter. SIP1 and Snail bind to partly overlapping promoter sequences and showed similar silencing effects. SIP1 can be induced by TGF-beta treatment and shows high expression in several E-cadherin-negative human carcinoma cell lines. Conditional expression of SIP1 in E-cadherin-positive MDCK cells abrogates E-cadherin-mediated intercellular adhesion and simultaneously induces invasion. SIP1 therefore appears to be a promoter of invasion in malignant epithelial tumors.
Insights
SIP1 (ZEB-2) protein downregulates E-cadherin transcription, promoting tumor invasion. This transcription factor binds E-cadherin promoter regions, impacting cell adhesion and driving malignancy in epithelial cancers.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Epithelial tumor progression often involves decreased E-cadherin expression.
- SIP1 (ZEB-2) is a zinc-finger protein interacting with Smad proteins and possessing DNA-binding activity.
Purpose of the Study:
- To investigate the role of SIP1 (ZEB-2) in regulating E-cadherin transcription.
- To determine if SIP1 (ZEB-2) influences cell adhesion and invasion in epithelial tumors.
Main Methods:
- Analyzing the effect of wild-type and mutated SIP1 on E-cadherin promoter activity.
- Investigating SIP1 and Snail binding sites on the E-cadherin promoter.
- Examining SIP1 expression in carcinoma cell lines and its effect in MDCK cells.
Main Results:
- Wild-type SIP1 downregulates E-cadherin transcription by binding to its promoter, unlike mutated SIP1.
- SIP1 and Snail bind to overlapping promoter regions and exhibit similar gene silencing effects.
- SIP1 expression, induced by TGF-beta, is high in E-cadherin-negative cell lines and promotes invasion in MDCK cells.
Conclusions:
- SIP1 (ZEB-2) acts as a transcriptional repressor of E-cadherin.
- SIP1-mediated downregulation of E-cadherin contributes to increased cell invasion in epithelial cancers.
- SIP1 is identified as a potential promoter of invasion in malignant epithelial tumors.