YAP1 is a prognostic marker and its inhibition reduces tumor progression in adrenocortical tumors

Background: Adrenocortical cancer (ACC) is rare and aggressive, with YAP1 overexpression associated with poor outcomes in pediatric patients. In this study, we investigated the mechanisms by which YAP1 drives ACC progression and explored it as a potential target therapy.

Methods: YAP1 expression and methylation in ACC were analyzed from pediatric and adult cohorts. The role of YAP1 on ACC progression was examined in vitro using an adrenocortical cell line. Also, was evaluated the YAP1's influence on beta-catenin. The effect of YAP1 pharmacological inhibition was assessed on tumor growth in a murine xenograft model of ACC.

Results: High YAP1 expression was associated with lower survival in all cohorts. YAP1 methylation signature associated with patients' prognosis. The inhibition of YAP1 reduced ACC cell viability through cell cycle arrest in the G0-G1 phase, inhibited the epithelial-mesenchymal transition, and cell invasion. YAP1 modulated beta-catenin protein levels and transcription activity, whereas beta-catenin partially mediated the effect of YAP1 on adrenocortical tumorigenesis. In vivo, verteporfin impaired tumor growth and Ki67 immunoreactivity in xenografts.

Conclusions: YAP1 is a potential novel prognostic marker in ACC patients. Its deregulation contributes to adrenocortical tumorigenesis partially through crosstalk between Hippo/YAP1 and Wnt/beta-catenin pathways. YAP1 inhibition is a new antitumor target.