E-cadherin is known to regulate cell–cell adhesion, but what regulates E-cadherin? Van Roy and colleagues now show that SIP1, a zinc finger protein with a Smad interaction domain, can repress the expression of E-cadherin and thereby function as a potent promoter of invasion.

Reporter assays showed that transcriptional repression of E-cadherin by SIP1 requires the amino- and carboxy-terminal zinc finger clusters of SIP1 and both E2 boxes in the E-cadherin promoter. By using a SIP1-inducible expression system and an E-cadherin positive cell line, the authors showed a strong correlation between SIP1 induction and E-cadherin repression. Likewise, northern blot analysis of several E-cadherin-positive and -negative cell lines revealed a strong inverse correlation between SIP1 and E-cadherin expression. As catenins are important for the formation of stable cell–cell contacts, the effect of SIP1 on the expression and localization of β-catenin was examined — neither was affected. Moreover, there was no evidence that SIP1 increases nuclear or cytosolic β-catenin-mediated signalling.

So what's the phenotypic consequence of inducing SIP1 expression in E-cadherin-positive epithelial cells? Cell–cell aggregation is abrogated, cell invasion into collagen type I gels increases and unidirectional cell migration decreases — all very desirable traits for a progressing epithelial tumour cell.