The deubiquitinating enzyme UCHL3 promotes anaplastic thyroid cancer progression and metastasis through Hippo signaling pathway

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.

Automated summary

In this study, the researchers identified ubiquitin carboxyl terminal hydrolase L3 (UCHL3) as a deubiquitylase of Yes-associated protein (YAP) in Anaplastic thyroid carcinoma (ATC). UCHL3 stabilizes YAP through its deubiquitylation activity, and its depletion leads to decreased ATC progression, stemness, metastasis, and increased sensitivity to chemotherapy. The study also revealed that TEAD4, which binds to YAP and DNA, activates UCHL3 transcription by binding to its promoter.