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β-arrestin-1 is a nuclear transcriptional regulator of endothelin-1-induced β-catenin signaling

Oncogene volume 32, pages 5066–5077 (2013)Cite this article

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Abstract

Despite the fundamental pathophysiological importance of β-catenin in tumor progression, the mechanism underlying its final transcriptional output has been partially elucidated. Here, we report that β-arrestin-1 (β-arr1) is an epigenetic regulator of endothelin (ET)-1-induced β-catenin signaling in epithelial ovarian cancer (EOC). In response to ET A receptor (ETAR) activation by ET-1, β-arr1 increases its nuclear translocation and direct binding to β-catenin. This in turn enhanced β-catenin nuclear accumulation and transcriptional activity, which was prevented by expressing a mutant β-arr1 incapable of nuclear distribution. β-arr1–β-catenin interaction controls β-catenin target gene expressions, such as ET-1, Axin 2, Matrix metalloproteinase 2, and Cyclin D1, by promoting histone deacetylase 1 (HDAC1) dissociation and the recruitment of p300 acetyltransferase on these promoter genes, resulting in enhanced H3 and H4 histone acetylation, and gene transcription, required for cell migration, invasion and epithelial-to-mesenchymal transition. These effects are abrogated by β-arr1 silencing or by mutant β-arr1, as well as by β-catenin or p300 silencing, confirming that nuclear β-arr1 forms a functional complex capable of regulating epigenetic changes in β-catenin-driven invasive behavior. In a murine orthotopic model of metastatic human EOC, silencing of β-arr1 or mutant β-arr1 expression, as well as ETAR blockade, inhibits metastasis. In human EOC tissues, β-arr1–β-catenin nuclear complexes are selectively enriched at β-catenin target gene promoters, correlating with tumor grade, confirming a direct in vivo β-arr1–β-catenin association at specific set of genes involved in EOC progression. Collectively, our study provides insights into how a β-arr1-mediated epigenetic mechanism controls β-catenin activity, unraveling new components required for its nuclear function in promoting metastasis.

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Acknowledgements

We gratefully acknowledge Valentina Caprara and Aldo Lupo for excellent technical assistance, Maria Vincenza Sarcone for secretarial assistance, Dr Maurizio Fanciulli for valuable comments, Dr Robert Lefkowitz (Howard Hughes Medical Institute, Duke University) for his insightful comments and for kindly providing β-arr1 expression vector; Dr Zhuohua Zhang (University of California San Diego School of Medicine, La Jolla, CA, USA) for ET-1 promoter reporter and its mutant control, and Dr Tania Merlino for the formal revision of the manuscript. This work was supported by the grant funded by the Associazione Italiana Ricerca sul Cancro.

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Authors and Affiliations

  1. Laboratory of Molecular Pathology, Regina Elena National Cancer Institute, Rome, Italy

    L Rosanò, R Cianfrocca, P Tocci, F Spinella, V Di Castro, P G Natali & A Bagnato

  2. Department of Haematology, Section of Experimental Immunotherapy, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy

    F Spadaro

  3. Laboratory of Experimental Chemotherapy, Regina Elena National Cancer Institute, Rome, Italy

    E Salvati & A M Biroccio

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Rosanò, L., Cianfrocca, R., Tocci, P. et al. β-arrestin-1 is a nuclear transcriptional regulator of endothelin-1-induced β-catenin signaling. Oncogene 32, 5066–5077 (2013). https://doi.org/10.1038/onc.2012.527

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