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

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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 β-catenin–T-cell factor (TCF)-4 transcription complexes that bind to the promoter of the TGF-β3 gene to increase its transcription. Subsequent transforming growth factor (TGF)-β3 signaling increases LEF-1 gene expression causing formation of β-catenin–lymphoid enhancer factor (LEF)-1 complexes that initiate EMT. TGF-β1 or TGF-β2 stimulates this signaling mechanism by up-regulating synthesis of Snail and Slug. TGF-β1- and TGF-β2-induced EMT were found to be TGF-β3 dependent, establishing essential roles for multiple TGF-β isoforms. Finally, we determined that β-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-β and TCF signaling molecules that confers loss of cell–cell adhesion and acquisition of the mesenchymal phenotype.