title: β-arrestin-1 is a nuclear transcriptional regulator of endothelin-1-induced β-catenin signaling.
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.
authors.affiliation: Laboratory of Molecular Pathology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Rosanò
authors.forename: R
authors.initials: R
authors.lastname: Cianfrocca
authors.forename: P
authors.initials: P
authors.lastname: Tocci
authors.forename: F
authors.initials: F
authors.lastname: Spinella
authors.forename: V
authors.initials: V
authors.lastname: Di Castro
authors.forename: F
authors.initials: F
authors.lastname: Spadaro
authors.forename: E
authors.initials: E
authors.lastname: Salvati
authors.forename: A M
authors.initials: AM
authors.lastname: Biroccio
authors.forename: P G
authors.initials: PG
authors.lastname: Natali
authors.forename: A
authors.initials: A
authors.lastname: Bagnato
mesh_terms: D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D060466:Axin Protein / Q000235:genetics; D000077216:Carcinoma, Ovarian Epithelial; D002467:Cell Nucleus / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics; D019332:Endothelin-1 / Q000378:metabolism*; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D008819:Mice, Nude; D009154:Mutation; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D044022:Receptor, Endothelin A / Q000378:metabolism; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
chemical_list: C000605253:ARRB1 protein, human; C491761:AXIN2 protein, human; C000605255:Arrb1 protein, mouse; D019390:Arrestins; D060466:Axin Protein; C530104:CCND1 protein, human; D019332:Endothelin-1; D006657:Histones; D044022:Receptor, Endothelin A; D051176:beta Catenin; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D019938:Cyclin D1; D020778:Matrix Metalloproteinase 2; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1