The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion

Transcriptional downregulation of E-cadherin appears to be an important eve nt in the progression of various epithelial tumors. SIP1 (ZEB-2) is a Smad- interacting, multi-zinc finger protein that shows specific DNA binding acti vity. Here, we report that expression of wildtype but not of mutated SIP1 d ownregulates mammalian E-cadherin transcription via binding to both conserv ed E2 boxes of the minimal E-cadherin promoter. SIP1 and Snail bind to part ly overlapping promoter sequences and showed similar silencing effects. SIP 1 can be induced by TGF-P treatment and shows high expression in several E- cadherin-negative human carcinoma cell lines. Conditional expression of SIP 1 in E-cadherin-positive MDCK cells abrogates E-cadherin-mediated intercell ular adhesion and simultaneously induces invasion. SIP1 therefore appears t o be a promoter of invasion in malignant epithelial tumors.