Loss of E-cadherin is a key initial step in the transdifferentiation of epithelial cells to a mesenchymal phenotype, which occurs when tumor epithelial cells invade into surrounding tissues. Expression of the nuclear factor ZEB1 induces an epithelial-to-mesenchymal transition and confers a metastatic phenotype on carcinomas by repressing the E-cadherin gene at the transcriptional level. In this study, we show that ZEB1 interacts with the SWI/SNF chromatin-remodeling protein BRG1 to regulate E-cadherin independently of CtBP, its traditional co-repressor. Blocking the interaction between ZEB1 and BRG1 induces expression of E-cadherin and downregulation of the mesenchymal marker vimentin. ZEB1 and BRG1 colocalize in E-cadherin-negative cells from cancer lines and in the stroma of normal colon. Colocalization of ZEB1 and BRG1 in epithelial cells is only found in those de-differentiated cells characterized by nuclear β-catenin staining at the invasive edge of the tumor. Our results identify ZEB1/BRG1 as a new transcriptional mechanism regulating E-cadherin expression and epithelial-to-mesenchymal transdifferentiation that may be involved during the initial stages of tumor invasion.