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

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.

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

“…A large number of studies have established a critical role for EPAC1 in the invasion and metastasis of several cancers including melanoma (45)(46)(47)(48)(49)(50)333), prostate cancer (42,362,688,711,713), ovarian cancer (62,855), pancreatic cancer (13,17,123,636,1095), cervical cancer (589), fibrosarcoma (399), and lung cancer (463,614). While the majority of reports suggest that EPAC1 activation promotes cancer cell migration and metastasis, few studies, using an EPAC-selective agonist 007, suggest that activation of EPAC1 inhibits cancer cell migration (62,362).…”

“…Genetic and pharmacological studies demonstrate that EPAC1 promotes pancreatic cancer cell migration and invasion through stimulating activation and trafficking of integrin ␤1 (13). Recent studies also suggest that EPAC signaling can stimulate the migration of cancer cells by inducing histone deacetylase 6 (HDAC6) expression (614), or by enhancing ␤-catenin nuclear translocation and ␤-catenin-dependent transcription (463) in lung cancer cells. While a diverse array of signaling pathways are involved in EPAC1-mediated cancer cell migration and invasion, most may ultimately converge and attribute this EPAC1 function to an integrin-dependent mechanism in various cancers (13,42,45,333,855).…”

“…"Clearly, the development of the first antagonists with (subtype) selectivity for EPAC represents another research milestone to ascribe biologic responses to EPAC" (915). Indeed, these selective EPAC2 inhibitors are becoming effective tools in probing isoform-specific EPAC functions (18,47,130,175,226,250,302,411,463,565,682,743,841,896,961,1114).…”

Function of cAMP scaffolds in obstructive lung disease: Focus on epithelial‐to‐mesenchymal transition and oxidative stress

“…In human alveolar epithelial cells, ezrin is highly associated with morphological changes, actin filament remodelling, and regulation of cell migration and invasion in EMT induced by TGF-β1 (Chen et al, 2014;Figure 2). Moreover, in tumour-related studies, overexpression of ezrin enhanced the metastatic potential, whereas the knockdown of ezrin inhibited cell migration and invasion (Huang et al, 2010;Jansen et al, 2016;Li et al, 2012). Interestingly, ezrin altered its intracellular localization from the apical membrane to the cytoplasm in lung cancers, thereby indicating that subcellular compartmentalization of ezrin is subject to alterations during cancer progression (Li et al, 2012).…”

“…There are two Epac isoforms, Epac1 and Epac2, which have distinct tissue expression patterns . Studies have demonstrated that gene expression of Epac1 but not Epac2 was increased by PGE 2 in lung epithelial A549 cells (Jansen et al, 2016), thereby emphasizing that Epac1 was involved in PGE 2 -induced EMT.…”