TGF-β drives epithelial-mesenchymal transition through δEF1-mediated downregulation of ESRP

Epithelial-mesenchymal transition (EMT) is a crucial event in wound healing, tissue repair and cancer progression in adult tissues. We have recently shown that transforming growth factor (TGF)-beta-induced EMT involves isoform switching of fibroblast growth factor receptors by alternative splicing. We performed a microarray-based analysis at single exon level to elucidate changes in splicing variants generated during TGF-beta-induced EMT, and found that TGF-beta induces broad alteration of splicing patterns by downregulating epithelial splicing regulatory proteins (ESRPs). This was achieved by TGF-beta-mediated upregulation of delta EF1 family proteins, delta EF1 and SIP1. delta EF1 and SIP1 each remarkably repressed ESRP2 transcription through binding to the ESRP2 promoter in NMuMG cells. Silencing of both delta EF1 and SIP1, but not either alone, abolished the TGF-beta-induced ESRP repression. The expression profiles of ESRPs were inversely related to those of delta EF1 and SIP in human breast cancer cell lines and primary tumor specimens. Further, overexpression of ESRPs in TGF-beta-treated cells resulted in restoration of the epithelial splicing profiles as well as attenuation of certain phenotypes of EMT. Therefore, delta EF1 family proteins repress the expression of ESRPs to regulate alternative splicing during TGF-beta-induced EMT and the progression of breast cancers. Oncogene (2012) 31, 3190-3201; doi:10.1038/onc.2011.493; published online 31 October 2011