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 ␤-catenin-T-cell factor (TCF)-4 transcription complexes that bind to the promoter of the TGF-␤3 gene to increase its transcription. Subsequent transforming growth factor (TGF)-␤3 signaling increases LEF-1 gene expression causing formation of ␤-catenin-lymphoid enhancer factor (LEF)-1 complexes that initiate EMT. TGF-␤1 or TGF-␤2 stimulates this signaling mechanism by up-regulating synthesis of Snail and Slug. TGF-␤1-and TGF-␤2-induced EMT were found to be TGF-␤3 dependent, establishing essential roles for multiple TGF-␤ isoforms. Finally, we determined that ␤-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-␤ and TCF signaling molecules that confers loss of cell-cell adhesion and acquisition of the mesenchymal phenotype.

Attenuation of the beta-catenin/TCF4 complex in colorectal cancer cells induces several growth-suppressive microRNAs that target cancer promoting genes

“…Finally, to substantiate the responsiveness of these three miRNAs to dnTCF expression, we repeated the dox-dnTCF4 experiment and also included the previously described isogenic DLD1 cell line carrying doxinducible dnTCF1 alleles (van de Wetering et al, 2002) (Supplementary Figure S3). TCF1 and TCF4 have nearly identical binding affinities in vitro, but differ in their regulation-selectivity of specific loci and by their in vivo expression patterns (Waterman, 2004;Gregorieff et al, 2005;Medici et al, 2008). We also included the known growth-suppressive miR-145 and miR-126 miRNAs in the analysis, and found that all five miRNAs were upregulated to varying degrees following dnTCF1/4 expression although miR-30e-3p and miR-574-3p were preferentially regulated by dnTCF4 (Figure 2b).…”

Bcl-2 Overexpression Induces a Partial Epithelial to Mesenchymal Transition and Promotes Squamous Carcinoma Cell Invasion and Metastasis

“…For example, the T-box transcription factor Tbx3, like snail and slug, was recently shown to downregulate the E-cadherin promoter (57). Similarly, β-catenin-LEF-1 complexes can directly promote EMT and acquisition of the mesenchymal phenotype without upstream signaling pathways involving snail family transcription factors (58). However, our study indicates that Bcl-2 overexpression regulates N-cadherin expression at the transcriptional level, and it will be important to identify the specific mechanism by which Bcl-2 upregulates N-cadherin expression.…”

Epithelial-mesenchymal transition during extravillous trophoblast differentiation

“…58 The TCF/ b-catenin complex is the key regulatory transcription factor of the Wnt signaling pathway, promoting multiple processes such as embryonic development, stem cell maintenance, differentiation and tumorigenesis. 59 EVT formation is associated with activation of canonical Wnt signaling, with localization of nuclear TCF-4 and b-catenin expression in the distal regions of the trophoblast cell columns and in invasive EVTs.…”