Molecular analyses of TGF-β-induced Epithelial-Mesenchymal Transition in oral cancer cells

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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 δEF-1 family proteins, ZEB1 and SIP1, is gradually increased by TGF-β with expression profiles reciprocal to that of E-cadherin. SIP1 or ZEB1 dramatically downregulated the transcription of E-cadherin in NMuMG cells through direct binding to the E-cadherin promoter. Silencing the expression of both SIP1 and ZEB1, but not either alone, by their specific siRNAs completely abolished TGF-β-induced E-cadherin repression. However, mesenchymal markers, including fibronectin, N-cadherin and vimentin, were not affected by knock-down of SIP1 and ZEB1. TGF-β induced the expression of Ets1, which in turn activated the ZEB1 promoter activity. Moreover, upregulation of SIP1 and ZEB1 by TGF-β was suppressed by knock-down of Ets1 expression. In addition, Id2 suppressed the TGF-β- and Ets1-induced upregulation of ZEB1. Taken together, these findings suggest that δEF-1 family proteins, SIP1 and ZEB1, are required, but not sufficient, for TGF-β-induced EMT, and that Ets1 induced by TGF-β may serve as an upstream transcriptional regulator of SIP1 and ZEB1.