Oncotarget

Research Papers:

Epac1 links prostaglandin E2 to β-catenin-dependent transcription during epithelial-to-mesenchymal transition

Sepp R. Jansen _, Wilfred J. Poppinga, Wim de Jager, Frank Lezoualc'h, Xiaodong Cheng, Thomas Wieland, Stephen J. Yarwood, Reinoud Gosens and Martina Schmidt

PDF  |  HTML  |  How to cite  |  Order a Reprint

Oncotarget. 2016; 7:46354-46370. https://doi.org/10.18632/oncotarget.10128

Metrics: PDF 1358 views  |   HTML 1652 views  |   ?  


Abstract

Sepp R. Jansen1,4, Wilfred J. Poppinga1, Wim de Jager1, Frank Lezoualc’h2, Xiaodong Cheng3, Thomas Wieland4, Stephen J. Yarwood5, Reinoud Gosens1, Martina Schmidt1

1Department of Molecular Pharmacology, Groningen Research Institute for Pharmacy (GRIP), University of Groningen, Groningen, The Netherlands

2Inserm UMR-1048, Institut des Maladies Métaboliques et Cardiovasculaires, Université Toulouse III, Toulouse, France

3Department of Integrative Biology & Pharmacology, Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas, Houston, TX, USA

4Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany

5School of Life Sciences, Heriot-Watt University, Edinburgh, Scotland

Correspondence to:

Sepp R. Jansen, email: sepp.jansen@medma.uni-heidelberg.de

Keywords: PGE2, Epac, β-catenin, Ezrin, EMT

Received: January 12, 2016    Accepted: June 02, 2016    Published: June 17, 2016

ABSTRACT

In epithelial cells, β-catenin is localized at cell-cell junctions where it stabilizes adherens junctions. When these junctions are disrupted, β-catenin can translocate to the nucleus where it functions as a transcriptional cofactor. Recent research has indicated that PGE2 enhances the nuclear function of β-catenin through cyclic AMP. Here, we aim to study the role of the cyclic AMP effector Epac in β-catenin activation by PGE2 in non-small cell lung carcinoma cells.

We show that PGE2 induces a down-regulation of E-cadherin, promotes cell migration and enhances β-catenin translocation to the nucleus. This results in β-catenin-dependent gene transcription. We also observed increased expression of Epac1. Inhibition of Epac1 activity using the CE3F4 compound or Epac1 siRNA abolished the effects of PGE2 on β-catenin. Further, we observed that Epac1 and β-catenin associate together. Expression of an Epac1 mutant with a deletion in the nuclear pore localization sequence prevents this association. Furthermore, the scaffold protein Ezrin was shown to be required to link Epac1 to β-catenin.

This study indicates a novel role for Epac1 in PGE2-induced EMT and subsequent activation of β-catenin.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 10128