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USP13 deubiquitinates and stabilizes cyclin D1 to promote gastric cancer cell cycle progression and cell proliferation

The reversible post-translational modifications of protein ubiquitination and deubiquitination play a crucial regulatory role in cellular homeostasis. Deubiquitinases (DUBs) are responsible for the removal of ubiquitin from the protein substrates. The dysregulation of the DUBs may give rise to the o...

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Autores principales: Ma, Cunying, Wang, Dandan, Tian, Zhuangfei, Gao, Wenrong, Zang, Yichen, Qian, Lilin, Xu, Xia, Jia, Jihui, Liu, Zhifang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10348911/
https://www.ncbi.nlm.nih.gov/pubmed/37311811
http://dx.doi.org/10.1038/s41388-023-02739-x
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author Ma, Cunying
Wang, Dandan
Tian, Zhuangfei
Gao, Wenrong
Zang, Yichen
Qian, Lilin
Xu, Xia
Jia, Jihui
Liu, Zhifang
author_facet Ma, Cunying
Wang, Dandan
Tian, Zhuangfei
Gao, Wenrong
Zang, Yichen
Qian, Lilin
Xu, Xia
Jia, Jihui
Liu, Zhifang
author_sort Ma, Cunying
collection PubMed
description The reversible post-translational modifications of protein ubiquitination and deubiquitination play a crucial regulatory role in cellular homeostasis. Deubiquitinases (DUBs) are responsible for the removal of ubiquitin from the protein substrates. The dysregulation of the DUBs may give rise to the occurrence and development of tumors. In this study, we investigated the gastric cancer (GC) data from the TCGA and GEO databases and found that ubiquitin-specific protease USP13 was significantly up-regulated in GC samples. The higher expression of USP13 was associated with the worse prognosis and shorter overall survival (OS) of GC patients. Enforced expression of USP13 in GC cells promoted the cell cycle progression and cell proliferation in an enzymatically dependent manner. Conversely, suppression of USP13 led to GC cell cycle arrest in G1 phase and the inhibition of cell proliferation. Nude mouse experiments indicated that depletion of USP13 in GC cells dramatically suppressed tumor growth in vivo. Mechanistically, USP13 physically bound to the N-terminal domain of cyclin D1 and removed its K48- but not K63-linked polyubiquitination chain, thereby stabilizing and increasing cyclin D1. Furthermore, re-expression of cyclin D1 partially reversed the cell cycle arrest and cell proliferation inhibition induced by USP13 depletion in GC cells. Additionally, USP13 protein abundance was positively correlated with the protein level of cyclin D1 in human GC tissues. Taken together, our data demonstrate that USP13 deubiquitinates and stabilizes cyclin D1, thereby promoting cell cycle progression and cell proliferation in GC. These findings suggest that USP13 might be a promising therapeutic target for the treatment of GC.
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spelling pubmed-103489112023-07-16 USP13 deubiquitinates and stabilizes cyclin D1 to promote gastric cancer cell cycle progression and cell proliferation Ma, Cunying Wang, Dandan Tian, Zhuangfei Gao, Wenrong Zang, Yichen Qian, Lilin Xu, Xia Jia, Jihui Liu, Zhifang Oncogene Article The reversible post-translational modifications of protein ubiquitination and deubiquitination play a crucial regulatory role in cellular homeostasis. Deubiquitinases (DUBs) are responsible for the removal of ubiquitin from the protein substrates. The dysregulation of the DUBs may give rise to the occurrence and development of tumors. In this study, we investigated the gastric cancer (GC) data from the TCGA and GEO databases and found that ubiquitin-specific protease USP13 was significantly up-regulated in GC samples. The higher expression of USP13 was associated with the worse prognosis and shorter overall survival (OS) of GC patients. Enforced expression of USP13 in GC cells promoted the cell cycle progression and cell proliferation in an enzymatically dependent manner. Conversely, suppression of USP13 led to GC cell cycle arrest in G1 phase and the inhibition of cell proliferation. Nude mouse experiments indicated that depletion of USP13 in GC cells dramatically suppressed tumor growth in vivo. Mechanistically, USP13 physically bound to the N-terminal domain of cyclin D1 and removed its K48- but not K63-linked polyubiquitination chain, thereby stabilizing and increasing cyclin D1. Furthermore, re-expression of cyclin D1 partially reversed the cell cycle arrest and cell proliferation inhibition induced by USP13 depletion in GC cells. Additionally, USP13 protein abundance was positively correlated with the protein level of cyclin D1 in human GC tissues. Taken together, our data demonstrate that USP13 deubiquitinates and stabilizes cyclin D1, thereby promoting cell cycle progression and cell proliferation in GC. These findings suggest that USP13 might be a promising therapeutic target for the treatment of GC. Nature Publishing Group UK 2023-06-13 2023 /pmc/articles/PMC10348911/ /pubmed/37311811 http://dx.doi.org/10.1038/s41388-023-02739-x Text en © The Author(s) 2023 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
Ma, Cunying
Wang, Dandan
Tian, Zhuangfei
Gao, Wenrong
Zang, Yichen
Qian, Lilin
Xu, Xia
Jia, Jihui
Liu, Zhifang
USP13 deubiquitinates and stabilizes cyclin D1 to promote gastric cancer cell cycle progression and cell proliferation
title USP13 deubiquitinates and stabilizes cyclin D1 to promote gastric cancer cell cycle progression and cell proliferation
title_full USP13 deubiquitinates and stabilizes cyclin D1 to promote gastric cancer cell cycle progression and cell proliferation
title_fullStr USP13 deubiquitinates and stabilizes cyclin D1 to promote gastric cancer cell cycle progression and cell proliferation
title_full_unstemmed USP13 deubiquitinates and stabilizes cyclin D1 to promote gastric cancer cell cycle progression and cell proliferation
title_short USP13 deubiquitinates and stabilizes cyclin D1 to promote gastric cancer cell cycle progression and cell proliferation
title_sort usp13 deubiquitinates and stabilizes cyclin d1 to promote gastric cancer cell cycle progression and cell proliferation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10348911/
https://www.ncbi.nlm.nih.gov/pubmed/37311811
http://dx.doi.org/10.1038/s41388-023-02739-x
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