Differential regulation of epithelial and mesenchymal markers by δEF1 proteins in epithelial-mesenchymal transition induced by TGF-β

Epithelial-mesenchymal transition (EMT), a crucial event in cancer progression and embryonic development, is induced by transforming growth factor (TGF)-beta in mouse mammary NMuMG epithelial cells. Id proteins have previously been reported to inhibit major features of TGF-beta-induced EMT. In this study, we show that expression of the delta EF1 family proteins, delta EF1 (ZEB1) and SIP1, is gradually increased by TGF-beta with expression profiles reciprocal to that of E-cadherin. SIP1 and delta EF1 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 delta EF1, but not either alone, completely abolished TGF-beta-induced E-cadherin repression. However, expression of mesenchymal markers, including fibronectin, N-cadherin, and vimentin, was not affected by knockdown of SIP1 and delta EF1. TGF-beta-induced the expression of Ets1, which in turn activated delta EF1 promoter activity. Moreover, up-regulation of SIP1 and delta EF1 expression by TGF-beta was suppressed by knockdown of Ets1 expression. In addition, Id2 suppressed the TGF-beta- and Ets1-induced up-regulation of delta EF1. Taken together, these findings suggest that the delta EF1 family proteins, SIP1 and delta EF1, are necessary, but not sufficient, for TGF-beta-induced EMT and that Ets1 induced by TGF-beta; may function as an upstream transcriptional regulator of SIP1 and delta EF1.