Yes-associated protein (YAP)是Hippo通路的主要关键效应因子之一，支持甲状腺癌（ATC）中异常YAP表达的机制尚未被表征。我们在这里确定泛素卡箱端水解酶L3（UCHL3）是ATC中YAP的真实去泛素化酶。UCHL3以去泛素化活性依赖方式稳定YAP。UCHL3的耗竭显著降低了ATC的进展、干细胞样和转移能力，并增加了细胞对化疗的敏感性。UCHL3的耗竭降低了ATC中YAP蛋白水平和YAP / TEAD靶基因的表达。UCHL3启动子分析揭示了TEAD4，通过该基因，YAP结合DNA，通过绑定UCHL3启动子来激活UCHL3转录。总的来说，我们的结果表明，UCHL3在稳定YAP中发挥关键作用，进而促进ATC的肿瘤发生，暗示UCHL3可能成为ATC治疗的潜在靶点。©2023年。作者，独家许可给ADMC Associazione Differenziamento e Morte Cellulare。

Yes-associated protein (YAP) is one of major key effectors of the Hippo pathway and the mechanism supporting abnormal YAP expression in Anaplastic thyroid carcinoma (ATC) remains to be characterized. Here, we identified ubiquitin carboxyl terminal hydrolase L3 (UCHL3) as a bona fide deubiquitylase of YAP in ATC. UCHL3 stabilized YAP in a deubiquitylation activity-dependent manner. UCHL3 depletion significantly decreased ATC progression, stem-like and metastasis, and increased cell sensitivity to chemotherapy. Depletion of UCHL3 decreased the YAP protein level and the expression of YAP/TEAD target genes in ATC. UCHL3 promoter analysis revealed that TEAD4, through which YAP bind to DNA, activated UCHL3 transcription by binding to the promoter of UCHL3. In general, our results demonstrated that UCHL3 plays a pivotal role in stabilizing YAP, which in turn facilitates tumorigenesis in ATC, suggesting that UCHL3 may prove to be a potential target for the treatment of ATC.© 2023. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.