Differential Regulation of Epithelial and Mesenchymal Markers by δEF1 Proteins in Epithelial–Mesenchymal Transition Induced by TGF-β

Abstract

Epithelial–mesenchymal transition (EMT), a crucial event in cancer progression and embryonic development, is induced by transforming growth factor (TGF)-β in mouse mammary NMuMG epithelial cells. Id proteins have previously been reported to inhibit major features of TGF-β–induced EMT. In this study, we show that expression of the δEF1 family proteins, δEF1 (ZEB1) and SIP1, is gradually increased by TGF-β with expression profiles reciprocal to that of E-cadherin. SIP1 and δEF1 each dramatically down-regulated the transcription of E-cadherin in NMuMG cells through direct binding to the E-cadherin promoter. Silencing of the expression of both SIP1 and δEF1, but not either alone, completely abolished TGF-β–induced E-cadherin repression. However, expression of mesenchymal markers, including fibronectin, N-cadherin, and vimentin, was not affected by knockdown of SIP1 and δEF1. TGF-β–induced the expression of Ets1, which in turn activated δEF1 promoter activity. Moreover, up-regulation of SIP1 and δEF1 expression by TGF-β was suppressed by knockdown of Ets1 expression. In addition, Id2 suppressed the TGF-β– and Ets1-induced up-regulation of δEF1. Taken together, these findings suggest that the δEF1 family proteins, SIP1 and δEF1, are necessary, but not sufficient, for TGF-β–induced EMT and that Ets1 induced by TGF-β may function as an upstream transcriptional regulator of SIP1 and δEF1.