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ATXN3 promotes prostate cancer progression by stabilizing YAP

BACKGROUND: Prostate cancer (PC) is the most common neoplasm and is the second leading cause of cancer-related deaths in men worldwide. The Hippo tumor suppressor pathway is highly conserved in mammals and plays an important role in carcinogenesis. YAP is one of major key effectors of the Hippo path...

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Autores principales: Wu, Longxiang, Ou, Zhenyu, Liu, Peihua, Zhao, Cheng, Tong, Shiyu, Wang, Ruizhe, Li, Yangle, Yuan, Junbin, Chen, Minfeng, Fan, Benyi, Zu, Xiongbing, Wang, Yongjie, Tang, Jianing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10286397/
https://www.ncbi.nlm.nih.gov/pubmed/37349820
http://dx.doi.org/10.1186/s12964-023-01073-9
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author Wu, Longxiang
Ou, Zhenyu
Liu, Peihua
Zhao, Cheng
Tong, Shiyu
Wang, Ruizhe
Li, Yangle
Yuan, Junbin
Chen, Minfeng
Fan, Benyi
Zu, Xiongbing
Wang, Yongjie
Tang, Jianing
author_facet Wu, Longxiang
Ou, Zhenyu
Liu, Peihua
Zhao, Cheng
Tong, Shiyu
Wang, Ruizhe
Li, Yangle
Yuan, Junbin
Chen, Minfeng
Fan, Benyi
Zu, Xiongbing
Wang, Yongjie
Tang, Jianing
author_sort Wu, Longxiang
collection PubMed
description BACKGROUND: Prostate cancer (PC) is the most common neoplasm and is the second leading cause of cancer-related deaths in men worldwide. The Hippo tumor suppressor pathway is highly conserved in mammals and plays an important role in carcinogenesis. YAP is one of major key effectors of the Hippo pathway. However, the mechanism supporting abnormal YAP expression in PC remains to be characterized. METHODS: Western blot was used to measure the protein expression of ATXN3 and YAP, while the YAP target genes were measured by real-time PCR. CCK8 assay was used to detect cell viability; transwell invasion assay was used to measure the invasion ability of PC. The xeno-graft tumor model was used for in vivo study. Protein stability assay was used to detect YAP protein degradation. Immuno-precipitation assay was used to detect the interaction domain between YAP and ATXN3. The ubiquitin-based Immuno-precipitation assays were used to detect the specific ubiquitination manner happened on YAP. RESULTS: In the present study, we identified ATXN3, a DUB enzyme in the ubiquitin-specific proteases family, as a bona fide deubiquitylase of YAP in PC. ATXN3 was shown to interact with, deubiquitylate, and stabilize YAP in a deubiquitylation activity-dependent manner. Depletion of ATXN3 decreased the YAP protein level and the expression of YAP/TEAD target genes in PC, including CTGF, ANKRD1 and CYR61. Further mechanistic study revealed that the Josephin domain of ATXN3 interacted with the WW domain of YAP. ATXN3 stabilized YAP protein via inhibiting K48-specific poly-ubiquitination process on YAP protein. In addition, ATXN3 depletion significantly decreased PC cell proliferation, invasion and stem-like properties. The effects induced by ATXN3 depletion could be rescued by further YAP overexpression. CONCLUSIONS: In general, our findings establish a previously undocumented catalytic role for ATXN3 as a deubiquitinating enzyme of YAP and provides a possible target for the therapy of PC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-023-01073-9.
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spelling pubmed-102863972023-06-23 ATXN3 promotes prostate cancer progression by stabilizing YAP Wu, Longxiang Ou, Zhenyu Liu, Peihua Zhao, Cheng Tong, Shiyu Wang, Ruizhe Li, Yangle Yuan, Junbin Chen, Minfeng Fan, Benyi Zu, Xiongbing Wang, Yongjie Tang, Jianing Cell Commun Signal Research BACKGROUND: Prostate cancer (PC) is the most common neoplasm and is the second leading cause of cancer-related deaths in men worldwide. The Hippo tumor suppressor pathway is highly conserved in mammals and plays an important role in carcinogenesis. YAP is one of major key effectors of the Hippo pathway. However, the mechanism supporting abnormal YAP expression in PC remains to be characterized. METHODS: Western blot was used to measure the protein expression of ATXN3 and YAP, while the YAP target genes were measured by real-time PCR. CCK8 assay was used to detect cell viability; transwell invasion assay was used to measure the invasion ability of PC. The xeno-graft tumor model was used for in vivo study. Protein stability assay was used to detect YAP protein degradation. Immuno-precipitation assay was used to detect the interaction domain between YAP and ATXN3. The ubiquitin-based Immuno-precipitation assays were used to detect the specific ubiquitination manner happened on YAP. RESULTS: In the present study, we identified ATXN3, a DUB enzyme in the ubiquitin-specific proteases family, as a bona fide deubiquitylase of YAP in PC. ATXN3 was shown to interact with, deubiquitylate, and stabilize YAP in a deubiquitylation activity-dependent manner. Depletion of ATXN3 decreased the YAP protein level and the expression of YAP/TEAD target genes in PC, including CTGF, ANKRD1 and CYR61. Further mechanistic study revealed that the Josephin domain of ATXN3 interacted with the WW domain of YAP. ATXN3 stabilized YAP protein via inhibiting K48-specific poly-ubiquitination process on YAP protein. In addition, ATXN3 depletion significantly decreased PC cell proliferation, invasion and stem-like properties. The effects induced by ATXN3 depletion could be rescued by further YAP overexpression. CONCLUSIONS: In general, our findings establish a previously undocumented catalytic role for ATXN3 as a deubiquitinating enzyme of YAP and provides a possible target for the therapy of PC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-023-01073-9. BioMed Central 2023-06-22 /pmc/articles/PMC10286397/ /pubmed/37349820 http://dx.doi.org/10.1186/s12964-023-01073-9 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Wu, Longxiang
Ou, Zhenyu
Liu, Peihua
Zhao, Cheng
Tong, Shiyu
Wang, Ruizhe
Li, Yangle
Yuan, Junbin
Chen, Minfeng
Fan, Benyi
Zu, Xiongbing
Wang, Yongjie
Tang, Jianing
ATXN3 promotes prostate cancer progression by stabilizing YAP
title ATXN3 promotes prostate cancer progression by stabilizing YAP
title_full ATXN3 promotes prostate cancer progression by stabilizing YAP
title_fullStr ATXN3 promotes prostate cancer progression by stabilizing YAP
title_full_unstemmed ATXN3 promotes prostate cancer progression by stabilizing YAP
title_short ATXN3 promotes prostate cancer progression by stabilizing YAP
title_sort atxn3 promotes prostate cancer progression by stabilizing yap
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10286397/
https://www.ncbi.nlm.nih.gov/pubmed/37349820
http://dx.doi.org/10.1186/s12964-023-01073-9
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