Functional loss of the cell-cell adhesion molecule E-cadherin is an essential 
event for epithelial-mesenchymal transition (EMT), a process that allows cell 
migration during embryonic development and tumour invasion. In most carcinomas, 
transcriptional repression has emerged as the main mechanism responsible for 
E-cadherin downregulation. Here, we report the identification of class I bHLH 
factor E2-2 (TCF4/ITF2) as a new EMT regulator. Both isoforms of E2-2 (E2-2A and 
E2-2B) induce a full EMT when overexpressed in MDCK cells but without affecting 
the tumorigenic properties of parental cells, in contrast to other EMT inducers, 
such as Snail1 or class I bHLH E47. E-cadherin repression mediated by E2-2 is 
indirect and independent of proximal E-boxes of the promoter. Knockdown studies 
indicate that E2-2 expression is dispensable for maintenance of the EMT driven 
by Snail1 and E47. Comparative gene-profiling analysis reveals that E2-2 factors 
induce similar, yet distinct, genetic programs to that induced by E47 in MDCK 
cells. These results, together with the embryonic expression pattern of Tcf4 and 
E2A (which encodes E12/E47), support a distinct role for E2-2 and suggest an 
interesting interplay between E-cadherin repressors in the regulation of 
physiological and pathological EMT processes.