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

Cell Death & Differentiation volume 30, pages 1247–1259 (2023)Cite this article

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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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Fig. 1: UCHL3 depletion decreases Hippo signaling activity in ATC cells.
Fig. 2: UCHL3 de-polyubiquitylates YAP.
Fig. 3: UCHL3 depletion inhibits ATC cell proliferation and migration.
Fig. 4: UCHL3 enhances tumorigenic capacity of anaplastic thyroid cancer stem cells.
Fig. 5: Increased YAP expression recovers the effect of UCHL3 depletion.
Fig. 6: TCID inhibits cell proliferation and migration.
Fig. 7: UCHL3 regulates the ATC cell response to chemotherapy.

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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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Authors and Affiliations

  1. Department of Liver Surgery, Xiangya Hospital, Central South University, Changsha, 410078, Hunan, China

    Jianing Tang, Liang Xiao & Ledu Zhou

  2. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China

    Jianing Tang

  3. Department of Breast and Thyroid Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China

    Jianing Tang, Qian Yang & Gaosong Wu

  4. Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Xiangya Hospital, Central South University, Changsha, 410078, Hunan, China

    Chao Mao & Yongguang Tao

  5. NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, Changsha, 410078, Hunan, China

    Chao Mao & Yongguang Tao

  6. Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410078, Hunan, China

    Desheng Xiao

  7. Department of Oncology, Institute of Medical Sciences, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Shuang Liu

  8. Department of Thoracic Surgery, Hunan Key Laboratory of Early Diagnosis and Precision Therapy in Lung Cancer and Hunan Key Laboratory of Tumor Models and Individualized Medicine, Second Xiangya Hospital, Central South University, Changsha, 410011, China

    Yongguang Tao

  9. Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410078, Hunan, China

    Yongguang Tao

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Contributions

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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Correspondence to Ledu Zhou, Gaosong Wu or Yongguang Tao.

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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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