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Phosphorylation of USP29 by CDK1 Governs TWIST1 Stability and Oncogenic Functions
Triple‐negative breast cancer (TNBC) is a highly lethal malignancy with limited therapy options. TWIST1, a key transcriptional factor of epithelial‐mesenchymal transition (EMT), contributes to self‐renewal of cancer stem‐like cells (CSCs), chemo‐resistance, metastasis, and TNBC‐related death. Howeve...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10104637/ https://www.ncbi.nlm.nih.gov/pubmed/36782089 http://dx.doi.org/10.1002/advs.202205873 |
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author | Guan, Tangming Li, Mei Song, Yan Chen, Jiayi Tang, Jiaxin Zhang, Caishi Wen, Yalei Yang, Xiao Huang, Lei Zhu, Yingjie Wang, Hongxian Ding, Ke Zheng, Junxia Zhang, Haoxing Liu, Tongzheng |
author_facet | Guan, Tangming Li, Mei Song, Yan Chen, Jiayi Tang, Jiaxin Zhang, Caishi Wen, Yalei Yang, Xiao Huang, Lei Zhu, Yingjie Wang, Hongxian Ding, Ke Zheng, Junxia Zhang, Haoxing Liu, Tongzheng |
author_sort | Guan, Tangming |
collection | PubMed |
description | Triple‐negative breast cancer (TNBC) is a highly lethal malignancy with limited therapy options. TWIST1, a key transcriptional factor of epithelial‐mesenchymal transition (EMT), contributes to self‐renewal of cancer stem‐like cells (CSCs), chemo‐resistance, metastasis, and TNBC‐related death. However, the mechanism by which TWIST1 is deregulated in TNBC remains elusive. Here, USP29 is identified as a bona fide deubiquitinase of TWIST1. The deubiquitination of TWIST1 catalyzed by USP29 is required for its stabilization and subsequent EMT and CSC functions in TNBC, thereby conferring chemotherapeutic resistance and metastasis. Furthermore, the results unexpectedly reveal that CDK1 functions as the direct USP29 activator. Mechanistically, CDK1‐mediated phosphorylation of USP29 is essential for its deubiquitinase activity toward TWIST1 and TWIST1 driven‐malignant phenotypes in TNBC, which could be markedly mitigated by the genetic ablation or pharmacological inhibition of CDK1. Moreover, the histological analyses show that CDK1 and USP29 are highly upregulated in TNBC samples, which positively correlate with the expression of TWIST1. Taken together, the findings reveal a previously unrecognized tumor‐promoting function and clinical significance of the CDK1‐USP29 axis through stabilizing TWIST1 and provide the preclinical evidence that targeting this axis is an appealing therapeutic strategy to conquer chemo‐resistance and metastasis in TNBC. |
format | Online Article Text |
id | pubmed-10104637 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-101046372023-04-15 Phosphorylation of USP29 by CDK1 Governs TWIST1 Stability and Oncogenic Functions Guan, Tangming Li, Mei Song, Yan Chen, Jiayi Tang, Jiaxin Zhang, Caishi Wen, Yalei Yang, Xiao Huang, Lei Zhu, Yingjie Wang, Hongxian Ding, Ke Zheng, Junxia Zhang, Haoxing Liu, Tongzheng Adv Sci (Weinh) Research Articles Triple‐negative breast cancer (TNBC) is a highly lethal malignancy with limited therapy options. TWIST1, a key transcriptional factor of epithelial‐mesenchymal transition (EMT), contributes to self‐renewal of cancer stem‐like cells (CSCs), chemo‐resistance, metastasis, and TNBC‐related death. However, the mechanism by which TWIST1 is deregulated in TNBC remains elusive. Here, USP29 is identified as a bona fide deubiquitinase of TWIST1. The deubiquitination of TWIST1 catalyzed by USP29 is required for its stabilization and subsequent EMT and CSC functions in TNBC, thereby conferring chemotherapeutic resistance and metastasis. Furthermore, the results unexpectedly reveal that CDK1 functions as the direct USP29 activator. Mechanistically, CDK1‐mediated phosphorylation of USP29 is essential for its deubiquitinase activity toward TWIST1 and TWIST1 driven‐malignant phenotypes in TNBC, which could be markedly mitigated by the genetic ablation or pharmacological inhibition of CDK1. Moreover, the histological analyses show that CDK1 and USP29 are highly upregulated in TNBC samples, which positively correlate with the expression of TWIST1. Taken together, the findings reveal a previously unrecognized tumor‐promoting function and clinical significance of the CDK1‐USP29 axis through stabilizing TWIST1 and provide the preclinical evidence that targeting this axis is an appealing therapeutic strategy to conquer chemo‐resistance and metastasis in TNBC. John Wiley and Sons Inc. 2023-02-13 /pmc/articles/PMC10104637/ /pubmed/36782089 http://dx.doi.org/10.1002/advs.202205873 Text en © 2023 The Authors. Advanced Science published by Wiley‐VCH GmbH https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Guan, Tangming Li, Mei Song, Yan Chen, Jiayi Tang, Jiaxin Zhang, Caishi Wen, Yalei Yang, Xiao Huang, Lei Zhu, Yingjie Wang, Hongxian Ding, Ke Zheng, Junxia Zhang, Haoxing Liu, Tongzheng Phosphorylation of USP29 by CDK1 Governs TWIST1 Stability and Oncogenic Functions |
title | Phosphorylation of USP29 by CDK1 Governs TWIST1 Stability and Oncogenic Functions |
title_full | Phosphorylation of USP29 by CDK1 Governs TWIST1 Stability and Oncogenic Functions |
title_fullStr | Phosphorylation of USP29 by CDK1 Governs TWIST1 Stability and Oncogenic Functions |
title_full_unstemmed | Phosphorylation of USP29 by CDK1 Governs TWIST1 Stability and Oncogenic Functions |
title_short | Phosphorylation of USP29 by CDK1 Governs TWIST1 Stability and Oncogenic Functions |
title_sort | phosphorylation of usp29 by cdk1 governs twist1 stability and oncogenic functions |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10104637/ https://www.ncbi.nlm.nih.gov/pubmed/36782089 http://dx.doi.org/10.1002/advs.202205873 |
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