YAP1 promoter-associated noncoding RNA affects Ewing sarcoma cell tumorigenicity by regulating YAP1 expression

Background: Ewing sarcomas (ESs) are aggressive paediatric tumours of bone and soft tissues afflicting children and adolescents. Despite current therapies having improved the 5-year survival rate to 70% in patients with localized disease, 25% of patients relapse and most have metastasis at diagnosis. Resistance to chemotherapy, together with the high propensity to metastasize, remain the main causes of treatment failure. Thus, identifying novel targets for alternative therapeutic approaches is urgently needed. Methods: Biochemical and functional analyses were carried out to elucidate the mechanism of regulation of YAP1 expression by pncRNA_YAP1-1 in ES cells. Results: Here, we identified a novel promoter-associated noncoding RNA, pncRNA_YAP1-1, transcribed from the YAP1 promoter in ES cells. We found that pncRNA_YAP1-1 level exerts antitumour effects on ES by destabilizing YAP1 protein. The molecular mechanism relies on the interaction of pncRNA_YAP1-1 with the RNA binding protein FUS, which stabilizes the transcript. Furthermore, pncRNA_YAP1-1 binding to TEAD impairs its interaction with YAP1, thus determining YAP1 translocation into the cytoplasm, its phosphorylation and degradation. Conclusions: Overall, our findings reveal a novel layer of regulation of YAP1 protein expression by pncRNA_YAP1-1 in Ewing sarcoma. Considering the role of YAP1 in therapy response and cell propensity to metastasize, our results indicate pncRNA_YAP1-1 as an actionable target that could be exploited to enhance chemotherapy efficacy in Ewing sarcoma. Significance: PncRNA_YAP1-1 counteracts the YAP1 oncogenic transcriptional program in Ewing sarcoma cells by interfering with YAP1-TEAD interaction and impairing YAP1 protein stability. These findings uncover a novel treatment option for Ewing sarcoma.