Format

Send to

Choose Destination
Nat Commun. 2019 Jul 19;10(1):3196. doi: 10.1038/s41467-019-11045-8.

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

Author information

1
Preclinical Models and New Therapeutic Agents Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Regina Elena National Cancer Institute, 00144, Rome, Italy.
2
Oncogenomic and Epigenetic Unit, IRCCS, Regina Elena National Cancer Institute, 00144, Rome, Italy.
3
Center for Translational Genomics and Bioinformatics, IRCCS, San Raffaele Scientific Institute, 20132, Milan, Italy.
4
Gynecologic Oncology, IRCCS, Regina Elena National Cancer Institute, 00144, Rome, Italy.
5
Gynecologic Oncology, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Catholic University of Rome, 00168, Rome, Italy.
6
Functional Genomics of Cancer Unit, Division of Experimental Oncology, IRCCS, San Raffaele Scientific Institute, 20132, Milan, Italy.
7
Oncogenomic and Epigenetic Unit, IRCCS, Regina Elena National Cancer Institute, 00144, Rome, Italy. giovanni.blandino@ifo.gov.it.
8
Preclinical Models and New Therapeutic Agents Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Regina Elena National Cancer Institute, 00144, Rome, Italy. annateresa.bagnato@ifo.gov.it.

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.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center