Abstract 1197: Endothelin-1 receptor/β-arrestin1 is an actionable node that regulates YAP/TAZ signaling and chemoresistance in high-grade ovarian cancer
Conferences
Overview
Research
Identity
Additional Document Info
View All
Overview
abstract
AbstractThe widespread activation of YAP and TAZ transcriptional regulators has been shown to promote tumor progression and resistance to anti-cancer therapies. Extensive studies have identified different upstream regulators of YAP/TAZ, including G-protein coupled receptor (GPCR). However how GPCR signals regulate YAP/TAZ puzzles have remained elusive. Among the GPCR, we reveal that the endothelin-1 (ET-1) receptor activates YAP/TAZ pathway in high-grade serous ovarian cancer (HG-SOC) sensitive and resistant cell lines and primary cultures. In HG-SOC cells, the aberrant activation of ET-1 receptor (ET-1R), promotes an enhanced nuclear shuttling of dephosphorylated YAP and TAZ in a time-dependent manner, through the scaffold protein β-arrestin1 (β-arr1). Interestingly, ET-1-induced YAP/TAZ nuclear accumulation is further improved in platinum-resistant cells and is prevented by expressing a mutant β-arr1 incapable of nuclear distribution. Moreover, the ET-1/ETAR axis activation induces the co-localization of β-arr1, YAP and TAZ in the nucleus. Mechanistically, in sensitive and to a greater extent in resistant cells, ET-1 induces the formation of a complex β-arr1/Trio, a Rho-Guanine nucleotide exchange factor family member, which dephosphorylates YAP, inducing its nuclear accumulation and the transcription of YAP/TAZ target genes. β-arr1, RhoA or Trio depletion, as well as the treatment with the dual ETAR/ETBR antagonist macitentan, significantly reduces RhoA GTPase activity and YAP nuclear translocation, suggesting that ET-1/ETAR axis regulates YAP/TAZ activity by driving β-arr1/Trio/RhoA pathway. According with these results, the ET-1-induced upregulation of YAP/TEAD target genes, such as CYR61, CTGF, ANKRD1 and EDN1, as well as TEAD transcriptional activity and cell invasion, are inhibited upon β-arr1, Trio, or YAP silencing, or macitentan treatment, demonstrating that β-arr1-mediated intersections are required for ET-1-induced YAP signaling. At the chromatin level, the activation of ET-1 axis promotes the recruitment of YAP, TEAD and β-arr1 on TEAD binding sites of CTGF, ANKRD1 and EDN1 promoters, an effect inhibited by macitentan treatment. These results indicate that β-arr1 can act as a transcription co-activator that bind TEAD thereby activating transcription of EDN1, which in turn, can sustain persistent YAP/TAZ activity through an autocrine loop. In murine orthotopic model of patient-derived xenograft (PDX) of HG-SOC, ET-1R blockade by macitentan, inhibits tumor growth, enhances the sensitivity to chemotherapy and reduces YAP and TEAD transcriptional activity. Altogether our results establish for the first time YAP/TAZ as critical downstream effectors of ET-1R/β-arr1 signaling, providing mechanistic insights that targeting ET-1R signaling overcomes YAP/TAZ driven platinum-based therapy failure in HG-SOC.Citation Format: Piera Tocci, Roberta Cianfrocca, Laura Rosanò, Rosanna Sestito, Valeriana Di Castro, Giovanni Blandino, Anna Bagnato. Endothelin-1 receptor/β-arrestin1 is an actionable node that regulates YAP/TAZ signaling and chemoresistance in high-grade ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1197. doi:10.1158/1538-7445.AM2017-1197
