Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cells


The adhesion protein E-cadherin plays a central part in the process of epithelial morphogenesis. Expression of this protein is downregulated during the acquisition of metastatic potential at late stages of epithelial tumour progression. There is evidence for a transcriptional blockage of E-cadherin gene expression in this process. Here we show that the transcription factor Snail, which is expressed by fibroblasts and some E-cadherin-negative epithelial tumour cell lines, binds to three E-boxes present in the human E-cadherin promoter and represses transcription of E-cadherin. Inhibition of Snail function in epithelial cancer cell lines lacking E-cadherin protein restores the expression of the E-cadherin gene.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Snail expression inversely correlates with E-cadherin mRNA levels.
Figure 2: Exogenous expression of mmSna downregulates E-cadherin mRNA levels.
Figure 3: Antisense repression of Snail mRNA restores E-cadherin expression.
Figure 4: mmSna blocks the activity of the –178/+92 fragment of the human E-cadherin promoter.
Figure 5: Mutation of the E-boxes impairs repression of the E-cadherin promoter by Snail.
Figure 6: Snail binds to the three E-boxes present in the –178/+92 fragment of the human E-cadherin promoter.

Similar content being viewed by others


  1. Vleminckx, K., Vakaet, L. Jr, Mareel, M., Fiers, W. & van Roy, F. Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 66, 107–119 (1991).

    Article  CAS  Google Scholar 

  2. Perl, A. K., Wilgenbus, P., Dahl, U., Semb, H. & Christofori, G. A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature 392, 190–193 (1998).

    Article  CAS  Google Scholar 

  3. Shiozaki, H., Oka, H., Inoue, M., Tamura, S. & Monden, M. E-cadherin mediated adhesion system in cancer cells. Cancer 77, 1605–1613 (1996).

    Article  CAS  Google Scholar 

  4. Hennig, G., Lowrick, O., Birchmeier, W. & Behrens, J. Mechanisms identified in the transcriptional control of epithelial gene expression. J. Biol. Chem. 271, 595–602 (1996).

    Article  CAS  Google Scholar 

  5. Ji, X., Woodard, A. S., Rimm, D. L. & Fearon, E. R. Transcriptional defects underlie loss of E-cadherin expression in breast cancer. Cell. Growth Differ. 8, 773–778 (1997).

    CAS  PubMed  Google Scholar 

  6. Giroldi, L. A. et al. Role of E boxes in the repression of E-cadherin expression. Biochem. Biophys. Res. Commun. 241, 453–458 (1997).

    Article  CAS  Google Scholar 

  7. Mauhin, V., Lutz, Y., Dennefeld, C. & Alberga, A. Definition of the DNA-binding site repertoire for the Drosophila transcription factor SNAIL. Nucleic Acids Res. 21, 3951–3957 (1993).

    Article  CAS  Google Scholar 

  8. Nakayama, H., Scott, I. C. & Cross, J. C. The transition to endoreduplication in trophoblast giant cells is regulated by the mSNA zinc finger transcription factor. Dev. Biol. 199, 150–163 (1998).

    Article  CAS  Google Scholar 

  9. Leptin, M. & Grunewald, B. Cell shape changes during gastrulation in Drosophila. Development 110, 73–84 (1990).

    CAS  PubMed  Google Scholar 

  10. Smith, D. E., del Amo, F. F. & Gridley, T. Isolation of Sna, a mouse gene homologous to the Drosophila genes snail and escargot: its expression pattern suggests multiple roles in postimplantation development. Development 116, 1033–1039 (1992).

    CAS  PubMed  Google Scholar 

  11. Oda, H., Tsukita, S., & Takeichi, M. Dynamic behaviour of the cadherin-based cell-cell adhesion system during Drosophila gastrulation. Dev. Biol. 203, 435–450 (1998).

    Article  CAS  Google Scholar 

  12. Sefton, M., Sanchez, S. & Nieto, M. A. Conserved and divergent roles for members of the Snail family of transcription factors in the chick and mouse embryo. Development 125, 3111–3121 (1998).

    CAS  PubMed  Google Scholar 

  13. Nieto, M. A., Sargent, M. G., Wilkinson, D. G. & Cooke, J. Control of cell behaviour during vertebrate development by Slug, a zinc finger gene. Science 264, 835–839 (1994).

    Article  CAS  Google Scholar 

  14. Grimes, H. L., Chan, T. O., Zweidler-McKay, P. A., Tong, B. & Tsichlis, P. N. The Gfi-1 proto-oncoprotein contains a novel transcriptional repressor domain, SNAG, and inhibits G1 arrest induced by interleukin-2 withdrawal. Mol. Cell. Biol. 16, 6263–6272 (1996).

    Article  CAS  Google Scholar 

  15. Birchmeier, C., Birchmeier, W. & Brand-Saberi, B. Epithelial-mesenchymal transitions in cancer progression. Acta Anat. 156, 217–226 (1996).

    Article  CAS  Google Scholar 

  16. Hay, E. D. An overview of epithelio-mesenchymal transformation. Acta Anat. 154, 8–20 (1995).

    Article  CAS  Google Scholar 

  17. Damjanov, I., Damjanov, A. & Damsky C. H. Developmentally regulated expression of the cell-cell adhesion glycoprotein Cell-CAM 120/80 in peri-implantation mouse embryos and extraembryonic membranes. Dev. Biol. 116, 194–202 (1986).

    Article  CAS  Google Scholar 

  18. Burdsal, C. A., Damsky, C. H. & Pedersen, R. A. The role of E-cadherin and integrins in mesoderm differentiation and migration at the mammalian primitive streak. Development 118, 829–844 (1993).

    CAS  PubMed  Google Scholar 

  19. Sorokin, L., Sonnenberg, A., Aumailley, M., Timpl, R., & Ekblom, P. Recognition of the laminin E8 cell-binding site by an integrin possessing the α6 integrin subunit is essential for epithelial polarization in developing kidney. J. Cell. Biol. 111, 1265–1273 (1990).

    Article  CAS  Google Scholar 

  20. Gossen, M. & Bujard, H. Tight control of gene expression in mammalian cells by tetracycline responsive promoters. Proc. Natl Acad. Sci. USA 89, 5547–5551 (1992).

    Article  CAS  Google Scholar 

  21. Schreiber, E., Matthias, P., Muller, M. M. & Schaffner, W. Rapid detection of octamer binding proteins with "mini-extracts" from a small number of cells. Nucleic Acids Res. 17, 6419 (1989).

    Article  CAS  Google Scholar 

  22. Rousseau, S., Renaud, J. & Ruiz-Carrillo, A. Basal expression of the histone H5 gene is controlled by positive and negative cis-acting sequences. Nucleic Acids Res. 17, 7495–7511 (1989).

    Article  CAS  Google Scholar 

Download references


We thank M. Garrido and C. Torns for technical help; J. Lloreta for assistance with electron microscopy; S. Gómez and S. Guaita for purification of fusion proteins; A. Fabra and F. Ulloa for reagents; R. Romero and D. Bueno for help with microscopy; F.X. Real for reagents, support and discussions during the study; and C. de Bolòs, M. Vilà and A. Meseguer for help in some critical moments. This work was supported by grants SAF 97-080 from Comisión Interministerial de Ciencia y Tecnología (CICYT) and from La Marató de TV3 to A.G.H. E.B. was supported by a predoctoral fellowship from CIRIT (Generalitat de Catalunya), and E.S. by funding from La Marató de TV3. J.B. was a recipient of a postdoctoral contract from the Ministerio de Educación.

Correspondence and requests for materials should be addressed to A.G.H. The human Snail cDNA sequence has been deposited in GenBank under accession number AF131208.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Antonio García de Herreros.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Batlle, E., Sancho, E., Francí, C. et al. The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2, 84–89 (2000).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing