Snail and Slug Promote Epithelial-Mesenchymal Transition through β-Catenin–T-Cell Factor-4-dependent Expression of Transforming Growth Factor-β3

Abstract

Members of the Snail family of transcription factors have been shown to induce epithelial-mesenchymal transition (EMT), a fundamental mechanism of embryogenesis and progressive disease. Here, we show that Snail and Slug promote formation of beta-catenin-T-cell factor (TCF)-4 transcription complexes that bind to the promoter of the TGF-beta 3 gene to increase its transcription. Subsequent transforming growth factor (TGF)-beta 3 signaling increases LEF-1 gene expression causing formation of beta-catenin-lymphoid enhancer factor (LEF)-1 complexes that initiate EMT. TGF-beta 1 or TGF-beta 2 stimulates this signaling mechanism by up-regulating synthesis of Snail and Slug. TGF-beta 1- and TGF-beta 2-induced EMT were found to be TGF-beta 3 dependent, establishing essential roles for multiple TGF-beta isoforms. Finally, we determined that beta-catenin-LEF-1 complexes can promote EMT without upstream signaling pathways. These findings provide evidence for a unified signaling mechanism driven by convergence of multiple TGF-beta and TCF signaling molecules that confers loss of cell-cell adhesion and acquisition of the mesenchymal phenotype.