E47 and Id1 interplay in epithelial-mesenchymal transition

PLoS One. 2013;8(3):e59948. doi: 10.1371/journal.pone.0059948. Epub 2013 Mar 26.

Abstract

E12/E47 proteins (encoded by E2A gene) are members of the class I basic helix-loop-helix (bHLH) transcription factors (also known as E proteins). E47 has been described as repressor of E-cadherin and inducer of epithelial-mesenchymal transition (EMT). We reported previously that EMT mediated by E47 in MDCK cells occurs with a concomitant overexpression of Id1 and Id3 proteins. Id proteins belong to class V of HLH factors that lack the basic domain; they dimerise with E proteins and prevent their DNA interaction, thus, acting as dominant negative of E proteins. Here, we show that E47 interacts with Id1 in E47 overexpressing MDCK cells that underwent a full EMT as well as in mesenchymal breast carcinoma and melanoma cell lines. By conducting chromatin immunoprecipitation assays we demonstrate that E47 binds directly to the endogenous E-cadherin promoter of mesenchymal MDCK-E47 cells in a complex devoid of Id1. Importantly, our data suggest that both E47 and Id1 are required to maintain the mesenchymal phenotype of MDCK-E47 cells. These data support the collaboration between E47 and Id1 in the maintenance of EMT by mechanisms independent of the dominant negative action of Id1 on E47 binding to E-cadherin promoter. Finally, the analysis of several N0 breast tumour series indicates that the expression of E47 and ID1 is significantly associated with the basal-like phenotype supporting the biological significance of the present findings.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Breast Neoplasms / metabolism
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Dogs
  • Epithelial-Mesenchymal Transition*
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • HEK293 Cells
  • Humans
  • Inhibitor of Differentiation Protein 1 / physiology*
  • Madin Darby Canine Kidney Cells
  • Male
  • Melanoma / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Transplantation
  • Phenotype
  • Transcription Factor 3 / physiology*

Substances

  • Cadherins
  • Inhibitor of Differentiation Protein 1
  • Transcription Factor 3

Grants and funding

This work was supported by the Spanish Ministry of Education and Science (SAF2007-63051; SAF2010-21143; Consolider Ingenio 2010 CDS07/00017) to A.C.; (SAF2007-63075 and SAF2010-20175) to G.M.B.; Comunidad de Madrid (S2010/BMD-2303) to A.C and G.M.B. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.