Snail Mediates E-Cadherin Repression by the Recruitment of the Sin3A/Histone Deacetylase 1 (HDAC1)/HDAC2 Complex

Abstract

The transcription factor Snail has been described as a direct repressor of E-cadherin expression during development and carcinogenesis; however, the specific mechanisms involved in this process remain largely unknown. Here we show that mammalian Snail requires histone deacetylase (HDAC) activity to repress E-cadherin promoter and that treatment with trichostatin A (TSA) is sufficient to block the repressor effect of Snail. Moreover, overexpression of Snail is correlated with deacetylation of histones H3 and H4 at the E-cadherin promoter, and TSA treatment in Snail-expressing cells reverses the acetylation status of histones. Additionally, we demonstrate that Snail interacts in vivo with the E-cadherin promoter and recruits HDAC activity. Most importantly, we demonstrate an interaction between Snail, histone deacetylase 1 (HDAC1) and HDAC2, and the corepressor mSin3A. This interaction is dependent on the SNAG domain of Snail, indicating that the Snail transcription factor mediates the repression by recruitment of chromatin-modifying activities, forming a multimolecular complex to repress E-cadherin expression. Our results establish a direct causal relationship between Snail-dependent repression of E-cadherin and the modification of chromatin at its promoter.

We thank E. Seto and R. N. Eisenman for providing reagents and A. Montes for her excellent technical assistance. Special thanks go to D. Megias and M. Cortés-Canteli for helping us with the confocal immunofluorescence analysis and to P. de la Peña-Ingelmo and J. Manzano for their suggestions in PCR experiments.

A. Cano's laboratory is supported by Spanish Ministry of Science and Technology grant SAF2001-2819 and by grants from the Instituto de Salud Carlos III (01/1074 and 031C03/10). M. Esteller's laboratory is supported by Spanish Ministry of Science and Technology grant SAF2001-0059 and the International Rett Syndrome Association. H. Peinado is a predoctoral fellow of the Spanish Ministry of Education, Culture and Sports. E. Ballestar is funded by the Ramón y Cajal Programme of the Spanish Ministry of Science and Technology.