β-arrestin1/YAP/mutant p53 complexes orchestrate the endothelin A receptor signaling in high-grade serous ovarian cancer

Piera Tocci, Roberta Cianfrocca, Valeriana Di Castro, Laura Rosanò, Andrea Sacconi, Sara Donzelli, Silvia Bonfiglio, Gabriele Bucci, Enrico Vizza, Gabriella Ferrandina, Giovanni Scambia, Giovanni Tonon, Giovanni Blandino, Anna Bagnato

Research output: Contribution to journalArticle

Abstract

The limited clinical response observed in high-grade serous ovarian cancer (HG-SOC) with high frequency of TP53 mutations (mutp53) might be related to mutp53-driven oncogenic pathway network. Here we show that β-arrestin1 (β-arr1), interacts with YAP, triggering its cytoplasmic-nuclear shuttling. This interaction allows β-arr1 to recruit mutp53 to the YAP-TEAD transcriptional complex upon activation of endothelin-1 receptors (ET-1R) in patient-derived HG-SOC cells and in cell lines bearing mutp53. In parallel, β-arr1 mediates the ET-1R-induced Trio/RhoA-dependent YAP nuclear accumulation. In the nucleus, ET-1 through β-arr1 orchestrates the tethering of YAP and mutp53 to YAP/mutp53 target gene promoters, including EDN1 that ensures persistent signals. Treatment of patient-derived xenografts reveals synergistic antitumoral and antimetastatic effects of the dual ET-1R antagonist macitentan in combination with cisplatinum, shutting-down the β-arr1-mediated YAP/mutp53 transcriptional programme. Furthermore, ETAR/β-arr1/YAP gene signature correlates with a worst prognosis in HG-SOC. These findings support effective combinatorial treatment for repurposing the ET-1R antagonists in HG-SOC.

Original languageEnglish
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Tocci, P., Cianfrocca, R., Di Castro, V., Rosanò, L., Sacconi, A., Donzelli, S., Bonfiglio, S., Bucci, G., Vizza, E., Ferrandina, G., Scambia, G., Tonon, G., Blandino, G., & Bagnato, A. (2019). β-arrestin1/YAP/mutant p53 complexes orchestrate the endothelin A receptor signaling in high-grade serous ovarian cancer. Nature Communications, 10(1). https://doi.org/10.1038/s41467-019-11045-8