11 pages, 6 figures.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.This work was supported by the Spanish Ministry of Education and Science (SAF2004-00361; SAF2007-63051) and the EV (MRTN 2004-005428) to A.C., Consolider-Ingenio 2010 CDC2007-00017 to A.C. and M.A.N., and the EU (MRTN 2004-005428) to A.C. and by the Fundación Mutua Madrileña (to G.M.B.). V.R.S. was supported by an FPU fellowship from the Spanish Ministry of Education and Science. G.M.B. is a junior investigator of the Ramón y Cajal Program 2004.Peer reviewe
