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Molecular mechanisms of epithelial to mesenchymal transition (EMT) induced by smad-interacting protein 1 (SIP1) in a squamous epidermoid carcinoma cell line

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posted on 15.12.2014, 10:33 by Jakob Mejlvang
Programmes of epithelial mesenchymal transition (EMT) are crucial for normal embryonic development and represent a potential oncogenic mechanism aberrantly exploited in oncogenesis. A hallmark of EMT is the inactivation of the E-cadherin adhesive complex, which constitutes the backbone of intercellular adhesion in epithelial tissue. Although transcriptional repressors of E-cadherin (e.g. SNAIL, SIP1, Slug, ZEB1) have been identified as potent inducers of EMT, little is still known about the EMT-programs they initiate. In this study, we show that ectopic expression of SIP1 in A431 squamous carcinoma cells induces EMT manifested by cell scattering, abrogation of E-cadherin mediated adhesion, loss of apical-basolateral bipolarity, increased invasiveness, down-regulation of epithelial (e.g. E-cadherin, Claudin-4, Keratin 13 and 15) and up-regulation of mesenchymal (e.g. Vimentin) markers. In addition to these classical features of EMT, we show that SIP1 in our model directly represses the cyclin D1 promoter activity and thereby inhibits proliferation through the pRb-pathway. Hence, a fully compromised pRb pathway is likely necessary in order for SIP1 to prosper in oncogenesis. Furthermore, using a SIP1 mutant (SIP1CIDmt) incapable of binding the co-repressor CtBP, we found that the intrinsic CtBP-interacting domain (CID) is necessary for the transcriptional repression of E-cadherin. However, expression of SIP1CIDmt successfully induces a morphological transformation in A431 cells similar to wild type SIP1 indicating that SIP1-mediated loss of epithelial phenotype is largely independent of the simultaneous down regulation of E-cadherin.


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Cancer Studies and Molecular Medicine

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University of Leicester

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