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 Yarwood, Reinoud Gosens, Martina Schmidt

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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.
Original languageEnglish
JournalOncotarget
Volume7
Issue number29
Early online date17 Jun 2016
DOIs
Publication statusPublished - Jul 2016

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