A SNAIL1-SMAD3/4 Transcriptional Repressor Complex Promotes TGF-beta Mediated Epithelial-Mesenchymal Transition

Nat Cell Biol. 2009 Aug;11(8):943-50. doi: 10.1038/ncb1905. Epub 2009 Jul 13.

Abstract

Epithelial-mesenchymal transition (EMT) is essential for organogenesis and is triggered during carcinoma progression to an invasive state. Transforming growth factor-beta (TGF-beta) 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-beta-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cadherins / genetics
  • Cell Line, Transformed
  • Cell Nucleus / metabolism
  • Chromatin Immunoprecipitation
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Humans
  • Intercellular Junctions / metabolism
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mesoderm / drug effects
  • Mesoderm / metabolism
  • Mesoderm / pathology
  • Mice
  • Mice, Inbred BALB C
  • Microscopy, Fluorescence
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Reverse Transcriptase Polymerase Chain Reaction
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism*
  • Smad4 Protein / genetics
  • Smad4 Protein / metabolism*
  • Snail Family Transcription Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transforming Growth Factor beta / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Cadherins
  • SMAD4 protein, human
  • SNAI1 protein, human
  • Smad3 Protein
  • Smad3 protein, mouse
  • Smad4 Protein
  • Snai1 protein, mouse
  • Snail Family Transcription Factors
  • Transcription Factors
  • Transforming Growth Factor beta