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

L. Rosanò, R. Cianfrocca, P. Tocci, F. Spinella, V. Di Castro, F. Spadaro, E. Salvati, A. M. Biroccio, P. G. Natali, A. Bagnato

Research output: Contribution to journalArticlepeer-review

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 ET AR 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.

Original languageEnglish
Pages (from-to)5066-5077
Number of pages12
JournalOncogene
Volume32
Issue number42
DOIs
Publication statusPublished - Oct 2013

Keywords

  • Beta-arrestin
  • Beta-catenin
  • Chromatin remodeling
  • Endothelin A receptor
  • Ovarian carcinoma

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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