Abstract 3086: α-arrestin-1 acts as a nuclear transcriptional regulator of endothelin A receptor signalling to promote ovarian cancer progression

Abstract

Abstract In epithelial ovarian cancer (EOC), endothelin (ET)-1/endothelin A receptor (ETAR) autocrine loop activates epithelial to mesenchymal transition (EMT) and malignant progression through the activation of β-catenin-driven transcriptional programs. Although it has been demonstrated that α-arrestin-1 (α-arr1) is involved in ETAR signalling acting as cytoplasmic scaffold protein, the specific contribution to ETAR-regulated EOC progression in the nuclear compartment remains undefined. In this study, we demonstrated that in response to ETAR activation by ET-1, endogenous as well as exogenous α-arr1 translocated to the nucleus in different EOC cell lines. To study a putative role of α-arr1 in controlling gene expression, we investigated the relationship of α-arr1 with β-catenin. We found that ET-1-driven α-arr1 nuclear translocation is associated with a nuclear translocation of with β-catenin and their physical interaction, as shown by microscopy and biochemical analysis. This nuclear complex, that include TCF4 transcription factor, is localized in ET-1-dependent manner on the promoter regions of specific β-catenin target genes, such as ET-1, matrix-metalloproteinase-2, and Cyclin D1, thus promoting their transcription. Gain/loss of function approaches as well as nuclear mutant α-arr1 expression demonstrated that this complex is critical for the recruitment and binding of p300 acetyltransferase on these promoters, resulting in enhanced H3 and H4 histone acetylation, enhanced promoter activity and gene expression, specifically required for ETAR-induced cell migration, invasion, and EMT. In a murine orthotopic model of metastatic human EOC, silencing of α-arr1 or expression of nuclear mutant α-arr1, as well as ETAR blockade, by the specific antagonist zibotentan, inhibits metastasis and intravasation. Finely, in human EOC tissues, α-arr1/β-catenin nuclear complexes are selectively enriched at specific gene promoters compared to non-tumoral ovarian tissues. Therefore, our study provides insights into how a nuclear α-arr1-mediated epigenetic mechanism controls β-catenin activity in response to ETAR activation, deciphering a novel function for α-arr1 as signal transducer for the nuclear compartmentalization of ETAR signalling in promoting tumor metastasis. Supported by AIRC, AstraZeneca Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3086. doi:1538-7445.AM2012-3086