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lncRNA BREA2 promotes metastasis by disrupting the WWP2-mediated ubiquitination of Notch1
Notch has been implicated in human cancers and is a putative therapeutic target. However, the regulation of Notch activation in the nucleus remains largely uncharacterized. Therefore, characterizing the detailed mechanisms governing Notch degradation will identify attractive strategies for treating...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9974429/ https://www.ncbi.nlm.nih.gov/pubmed/36795754 http://dx.doi.org/10.1073/pnas.2206694120 |
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author | Zhang, Zhen Lu, Yun-xin Liu, Fangzhou Sang, Lingjie Shi, Chengyu Xie, Shaofang Bian, Weixiang Yang, Jie-cheng Yang, Zuozhen Qu, Lei Chen, Shi-yi Li, Jun Yang, Lu Yan, Qingfeng Wang, Wenqi Fu, Peifen Shao, Jianzhong Li, Xu Lin, Aifu |
author_facet | Zhang, Zhen Lu, Yun-xin Liu, Fangzhou Sang, Lingjie Shi, Chengyu Xie, Shaofang Bian, Weixiang Yang, Jie-cheng Yang, Zuozhen Qu, Lei Chen, Shi-yi Li, Jun Yang, Lu Yan, Qingfeng Wang, Wenqi Fu, Peifen Shao, Jianzhong Li, Xu Lin, Aifu |
author_sort | Zhang, Zhen |
collection | PubMed |
description | Notch has been implicated in human cancers and is a putative therapeutic target. However, the regulation of Notch activation in the nucleus remains largely uncharacterized. Therefore, characterizing the detailed mechanisms governing Notch degradation will identify attractive strategies for treating Notch-activated cancers. Here, we report that the long noncoding RNA (lncRNA) BREA2 drives breast cancer metastasis by stabilizing the Notch1 intracellular domain (NICD1). Moreover, we reveal WW domain containing E3 ubiquitin protein ligase 2 (WWP2) as an E3 ligase for NICD1 at K1821 and a suppressor of breast cancer metastasis. Mechanistically, BREA2 impairs WWP2–NICD1 complex formation and in turn stabilizes NICD1, leading to Notch signaling activation and lung metastasis. BREA2 loss sensitizes breast cancer cells to inhibition of Notch signaling and suppresses the growth of breast cancer patient-derived xenograft tumors, highlighting its therapeutic potential in breast cancer. Taken together, these results reveal the lncRNA BREA2 as a putative regulator of Notch signaling and an oncogenic player driving breast cancer metastasis. |
format | Online Article Text |
id | pubmed-9974429 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-99744292023-08-16 lncRNA BREA2 promotes metastasis by disrupting the WWP2-mediated ubiquitination of Notch1 Zhang, Zhen Lu, Yun-xin Liu, Fangzhou Sang, Lingjie Shi, Chengyu Xie, Shaofang Bian, Weixiang Yang, Jie-cheng Yang, Zuozhen Qu, Lei Chen, Shi-yi Li, Jun Yang, Lu Yan, Qingfeng Wang, Wenqi Fu, Peifen Shao, Jianzhong Li, Xu Lin, Aifu Proc Natl Acad Sci U S A Biological Sciences Notch has been implicated in human cancers and is a putative therapeutic target. However, the regulation of Notch activation in the nucleus remains largely uncharacterized. Therefore, characterizing the detailed mechanisms governing Notch degradation will identify attractive strategies for treating Notch-activated cancers. Here, we report that the long noncoding RNA (lncRNA) BREA2 drives breast cancer metastasis by stabilizing the Notch1 intracellular domain (NICD1). Moreover, we reveal WW domain containing E3 ubiquitin protein ligase 2 (WWP2) as an E3 ligase for NICD1 at K1821 and a suppressor of breast cancer metastasis. Mechanistically, BREA2 impairs WWP2–NICD1 complex formation and in turn stabilizes NICD1, leading to Notch signaling activation and lung metastasis. BREA2 loss sensitizes breast cancer cells to inhibition of Notch signaling and suppresses the growth of breast cancer patient-derived xenograft tumors, highlighting its therapeutic potential in breast cancer. Taken together, these results reveal the lncRNA BREA2 as a putative regulator of Notch signaling and an oncogenic player driving breast cancer metastasis. National Academy of Sciences 2023-02-16 2023-02-21 /pmc/articles/PMC9974429/ /pubmed/36795754 http://dx.doi.org/10.1073/pnas.2206694120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Zhang, Zhen Lu, Yun-xin Liu, Fangzhou Sang, Lingjie Shi, Chengyu Xie, Shaofang Bian, Weixiang Yang, Jie-cheng Yang, Zuozhen Qu, Lei Chen, Shi-yi Li, Jun Yang, Lu Yan, Qingfeng Wang, Wenqi Fu, Peifen Shao, Jianzhong Li, Xu Lin, Aifu lncRNA BREA2 promotes metastasis by disrupting the WWP2-mediated ubiquitination of Notch1 |
title | lncRNA BREA2 promotes metastasis by disrupting the WWP2-mediated ubiquitination of Notch1 |
title_full | lncRNA BREA2 promotes metastasis by disrupting the WWP2-mediated ubiquitination of Notch1 |
title_fullStr | lncRNA BREA2 promotes metastasis by disrupting the WWP2-mediated ubiquitination of Notch1 |
title_full_unstemmed | lncRNA BREA2 promotes metastasis by disrupting the WWP2-mediated ubiquitination of Notch1 |
title_short | lncRNA BREA2 promotes metastasis by disrupting the WWP2-mediated ubiquitination of Notch1 |
title_sort | lncrna brea2 promotes metastasis by disrupting the wwp2-mediated ubiquitination of notch1 |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9974429/ https://www.ncbi.nlm.nih.gov/pubmed/36795754 http://dx.doi.org/10.1073/pnas.2206694120 |
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