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OTUD6A promotes prostate tumorigenesis via deubiquitinating Brg1 and AR

Ovarian tumor (OTU) subfamily deubiquitinases are involved in various cellular processes, such as inflammation, ferroptosis and tumorigenesis; however, their pathological roles in prostate cancer (PCa) remain largely unexplored. In this study, we observed that several OTU members displayed genomic a...

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Autores principales: Fu, Xuhong, Zhao, Junjie, Yu, Guopeng, Zhang, Xiaomin, Sun, Jie, Li, Lingmeng, Yin, Jingyi, Niu, Yinan, Ren, Shancheng, Zhu, Yasheng, Xu, Bin, Huang, Liyu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8888634/
https://www.ncbi.nlm.nih.gov/pubmed/35233061
http://dx.doi.org/10.1038/s42003-022-03133-1
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author Fu, Xuhong
Zhao, Junjie
Yu, Guopeng
Zhang, Xiaomin
Sun, Jie
Li, Lingmeng
Yin, Jingyi
Niu, Yinan
Ren, Shancheng
Zhu, Yasheng
Xu, Bin
Huang, Liyu
author_facet Fu, Xuhong
Zhao, Junjie
Yu, Guopeng
Zhang, Xiaomin
Sun, Jie
Li, Lingmeng
Yin, Jingyi
Niu, Yinan
Ren, Shancheng
Zhu, Yasheng
Xu, Bin
Huang, Liyu
author_sort Fu, Xuhong
collection PubMed
description Ovarian tumor (OTU) subfamily deubiquitinases are involved in various cellular processes, such as inflammation, ferroptosis and tumorigenesis; however, their pathological roles in prostate cancer (PCa) remain largely unexplored. In this study, we observed that several OTU members displayed genomic amplification in PCa, among which ovarian tumor deubiquitinase 6A (OTUD6A) amplified in the top around 15–20%. Further clinical investigation showed that the OTUD6A protein was highly expressed in prostate tumors, and increased OTUD6A expression correlated with a higher biochemical recurrence risk after prostatectomy. Biologically, wild-type but not a catalytically inactive mutant form of OTUD6A was required for PCa cell progression. In vivo experiments demonstrated that OTUD6A oligonucleotides markedly suppressed prostate tumorigenesis in Pten(PC−/−) mice and patient-derived xenograft (PDX) models. Mechanistically, the SWI/SNF ATPase subunit Brg1 and the nuclear receptor AR (androgen receptor) were identified as essential substrates for OTUD6A in PCa cells by a mass spectrometry (MS) screening approach. Furthermore, OTUD6A stabilized these two proteins by erasing the K27-linked polyubiquitination of Brg1 and K11-linked polyubiquitination of AR. OTUD6A amplification exhibited strong mutual exclusivity with mutations in the tumor suppressors FBXW7 and SPOP. Collectively, our results indicate the therapeutic potential of targeting OTUD6A as a deubiquitinase of Brg1 and AR for PCa treatment.
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spelling pubmed-88886342022-03-17 OTUD6A promotes prostate tumorigenesis via deubiquitinating Brg1 and AR Fu, Xuhong Zhao, Junjie Yu, Guopeng Zhang, Xiaomin Sun, Jie Li, Lingmeng Yin, Jingyi Niu, Yinan Ren, Shancheng Zhu, Yasheng Xu, Bin Huang, Liyu Commun Biol Article Ovarian tumor (OTU) subfamily deubiquitinases are involved in various cellular processes, such as inflammation, ferroptosis and tumorigenesis; however, their pathological roles in prostate cancer (PCa) remain largely unexplored. In this study, we observed that several OTU members displayed genomic amplification in PCa, among which ovarian tumor deubiquitinase 6A (OTUD6A) amplified in the top around 15–20%. Further clinical investigation showed that the OTUD6A protein was highly expressed in prostate tumors, and increased OTUD6A expression correlated with a higher biochemical recurrence risk after prostatectomy. Biologically, wild-type but not a catalytically inactive mutant form of OTUD6A was required for PCa cell progression. In vivo experiments demonstrated that OTUD6A oligonucleotides markedly suppressed prostate tumorigenesis in Pten(PC−/−) mice and patient-derived xenograft (PDX) models. Mechanistically, the SWI/SNF ATPase subunit Brg1 and the nuclear receptor AR (androgen receptor) were identified as essential substrates for OTUD6A in PCa cells by a mass spectrometry (MS) screening approach. Furthermore, OTUD6A stabilized these two proteins by erasing the K27-linked polyubiquitination of Brg1 and K11-linked polyubiquitination of AR. OTUD6A amplification exhibited strong mutual exclusivity with mutations in the tumor suppressors FBXW7 and SPOP. Collectively, our results indicate the therapeutic potential of targeting OTUD6A as a deubiquitinase of Brg1 and AR for PCa treatment. Nature Publishing Group UK 2022-03-01 /pmc/articles/PMC8888634/ /pubmed/35233061 http://dx.doi.org/10.1038/s42003-022-03133-1 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Fu, Xuhong
Zhao, Junjie
Yu, Guopeng
Zhang, Xiaomin
Sun, Jie
Li, Lingmeng
Yin, Jingyi
Niu, Yinan
Ren, Shancheng
Zhu, Yasheng
Xu, Bin
Huang, Liyu
OTUD6A promotes prostate tumorigenesis via deubiquitinating Brg1 and AR
title OTUD6A promotes prostate tumorigenesis via deubiquitinating Brg1 and AR
title_full OTUD6A promotes prostate tumorigenesis via deubiquitinating Brg1 and AR
title_fullStr OTUD6A promotes prostate tumorigenesis via deubiquitinating Brg1 and AR
title_full_unstemmed OTUD6A promotes prostate tumorigenesis via deubiquitinating Brg1 and AR
title_short OTUD6A promotes prostate tumorigenesis via deubiquitinating Brg1 and AR
title_sort otud6a promotes prostate tumorigenesis via deubiquitinating brg1 and ar
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8888634/
https://www.ncbi.nlm.nih.gov/pubmed/35233061
http://dx.doi.org/10.1038/s42003-022-03133-1
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