A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-β mediated epithelial-mesenchymal transition

By T. Vincent, E. Neve, Jill R. Johnson, A. Kukalev, F. Rojo, J. Albanell, K. Pietras, I. Virtanen, L. Philipson, P. Leopold and 5 more. Nature Cell Biology, 2009

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Epithelial–mesenchymal transition (EMT) is essential for organogenesis and is triggered during carcinoma progression to an invasive state. Transforming growth factor-β (TGF-β) cooperates with signalling pathways, such as Ras and Wnt, to induce EMT, but the molecular mechanisms are not clear. Here, we report that SMAD3 and SMAD4 interact and form a complex with SNAIL1, a transcriptional repressor and promoter of EMT. The SNAIL1–SMAD3/4 complex was targeted to the gene promoters of CAR, a tight-junction protein, and E-cadherin during TGF-β-driven EMT in breast epithelial cells. SNAIL1 and SMAD3/4 acted as co-repressors of CAR, occludin, claudin-3 and E-cadherin promoters in transfected cells. Conversely, co-silencing of SNAIL1 and SMAD4 by siRNA inhibited repression of CAR and occludin during EMT. Moreover, loss of CAR and E-cadherin correlated with nuclear co-expression of SNAIL1 and SMAD3/4 in a mouse model of breast carcinoma and at the invasive fronts of human breast cancer. We propose that activation of a SNAIL1–SMAD3/4 transcriptional complex represents a mechanism of gene repression during EMT.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/596308ccd66e769832e9947233a1b7fdbde9dde8

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Citations in the corpus

Dynamic EMT: a multi‐tool for tumor progression (2021, positive): “Initial TGF b receptor activation in breast or skin cancer results in transcriptional activation of SNAI 1 , combined with sumoylation of SNAIL at K 234 fostering SMAD/SNAIL complex formation that promotes EMT (Hoot et al , 2008 ; Vincent et al , 2009 ; Gudey et al , 2017 ) (Fig 4 B).”
Signaling mechanisms of the epithelial-mesenchymal transition (2014, background): “Complexes of R-SMADs are capable of binding directly to the promoter of SNAI1 to induce its transcription, and can form complexes with Snail1 to suppress the expression of genes encoding E-cadherin and occludin (98, 99).”
The Role of Snail in EMT and Tumorigenesis (2013, background): “This complex targets the adjacent E-boxes and Smadbinding elements in genes encoding junction proteins such as E-cadherin, CAR and occludin, resulting in genes repression [36].”
Epithelial-mesenchymal transitions in development and disease. (2009, background): “The expression of Snail1, Snail2, Twist, and Id2 is controlled during TGFβ-induced EMT by the highmobility group protein HMGA2, which behaves as an integrator of TGFβ signaling by using Snail1 as its downstream master effector (Thuault et al., 2008).”
TGF-&bgr; signaling and epithelial–mesenchymal transition in cancer progression (2013, background): “com subsequently, an active complex formed by Smad3/ Smad4 and Snail can bind to regulatory promoter sequences of the genes encoding the epithelial junction proteins E-cadherin and occludin, leading to TGF-b-induced repression of their expression [22].”