Abstract
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.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China [82072594, YT; 82073097, 81874139, SL; 82002916, CM; 82073136, 81772927, DX; 82203160, JT], the China Postdoctoral Science Foundation [2019M652804, CM; 2022M713531, JT], the Natural Science Foundation of Hunan Province [2022JJ40815, JT; 2020JJ5790, CM], the Hunan Provincial Key Area R&D Programs [2019SK2253, YT], the Science and Technology Innovation Program of Hunan Province [2022RC3072 (YT)], and the Central South University Research Program of Advanced Interdisciplinary Studies (2023QYJC030, YT).
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GW and YT designed and supervised the research. JT, QY, CM, LZ, DX, SL, GW and YT performed research and provided helpful discussions. JT, QY, CM, LZ, DX, SL, GW and YT analyzed and interpreted the data. DX conducted pathology evaluations. All authors reviewed and edited the manuscript. KH contributed to all aspects of the study. QY performed animal model experiments. JT had a primary role in interpreting and organizing the data as well as writing the manuscript.
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Tang, J., Yang, Q., Mao, C. et al. The deubiquitinating enzyme UCHL3 promotes anaplastic thyroid cancer progression and metastasis through Hippo signaling pathway. Cell Death Differ 30, 1247–1259 (2023). https://doi.org/10.1038/s41418-023-01134-z
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DOI: https://doi.org/10.1038/s41418-023-01134-z
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