Enhancer cooperativity as a novel mechanism underlying the transcriptional regulation of E-cadherin during mesenchymal to epithelial transition

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Alotaibi H., Basilicata M. F., Shehwana H., Kosowan T., Schreck I., Braeutigam C., ...More

BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS, vol.1849, no.6, pp.731-742, 2015 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 1849 Issue: 6
  • Publication Date: 2015
  • Doi Number: 10.1016/j.bbagrm.2015.01.005
  • Journal Name: BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.731-742
  • Keywords: Cadherins, Grhl3, Hnf4 alpha, Transforming growth factor beta, Development, Cancer, GENE, EXPRESSION, ELEMENTS, SNAIL, BETA, ENDODERM, FAMILY, TISSUE, HNF-4
  • Dokuz Eylül University Affiliated: Yes

Abstract

Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) highlight crucial steps during embryogenesis and tumorigenesis. Induction of dramatic changes in gene expression and cell features is reflected by modulation of Cdh1 (E-cadherin) expression. We show that Cdh1 activity during MET is governed by two enhancers at + 7.8 kb and at + 11.5 kb within intron 2 that are activated by binding of Grhl3 and Hnf4 alpha, respectively. Recruitment of Grhl3 and Hnf4 alpha to the enhancers is crucial for activating Cdh1 and accomplishing MET in non-tumorigenic mouse mammary gland cells (NMuMG). Moreover, the two enhancers cooperate via Grhl3 and Hnf4 alpha binding, induction of DNA-looping and clustering at the promoter to orchestrate E-cadherin re-expression. Our results provide novel insights into the cellular mechanisms whereby cells respond to MET signals and re-establish an epithelial phenotype by enhancer cooperativity. A general importance of our findings including MET-mediated colonization of metastasizing tumor cells is suggested. (C) 2015 Elsevier B.V. All rights reserved.