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Targeting USP2 regulation of VPRBP-mediated degradation of p53 and PD-L1 for cancer therapy
Since Mdm2 (Mouse double minute 2) inhibitors show serious toxicity in clinic studies, different approaches to achieve therapeutic reactivation of p53-mediated tumor suppression in cancers need to be explored. Here, we identify the USP2 (ubiquitin specific peptidase 2)-VPRBP (viral protein R binding...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10079682/ https://www.ncbi.nlm.nih.gov/pubmed/37024504 http://dx.doi.org/10.1038/s41467-023-37617-3 |
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author | Yi, Jingjie Tavana, Omid Li, Huan Wang, Donglai Baer, Richard J. Gu, Wei |
author_facet | Yi, Jingjie Tavana, Omid Li, Huan Wang, Donglai Baer, Richard J. Gu, Wei |
author_sort | Yi, Jingjie |
collection | PubMed |
description | Since Mdm2 (Mouse double minute 2) inhibitors show serious toxicity in clinic studies, different approaches to achieve therapeutic reactivation of p53-mediated tumor suppression in cancers need to be explored. Here, we identify the USP2 (ubiquitin specific peptidase 2)-VPRBP (viral protein R binding protein) axis as an important pathway for p53 regulation. Like Mdm2, VPRBP is a potent repressor of p53 but VPRBP stability is controlled by USP2. Interestingly, the USP2-VPRBP axis also regulates PD-L1 (programmed death-ligand 1) expression. Strikingly, the combination of a small-molecule USP2 inhibitor and anti-PD1 monoclonal antibody leads to complete regression of the tumors expressing wild-type p53. In contrast to Mdm2, knockout of Usp2 in mice has no obvious effect in normal tissues. Moreover, no obvious toxicity is observed upon the USP2 inhibitor treatment in vivo as Mdm2-mediated regulation of p53 remains intact. Our study reveals a promising strategy for p53-based therapy by circumventing the toxicity issue. |
format | Online Article Text |
id | pubmed-10079682 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-100796822023-04-08 Targeting USP2 regulation of VPRBP-mediated degradation of p53 and PD-L1 for cancer therapy Yi, Jingjie Tavana, Omid Li, Huan Wang, Donglai Baer, Richard J. Gu, Wei Nat Commun Article Since Mdm2 (Mouse double minute 2) inhibitors show serious toxicity in clinic studies, different approaches to achieve therapeutic reactivation of p53-mediated tumor suppression in cancers need to be explored. Here, we identify the USP2 (ubiquitin specific peptidase 2)-VPRBP (viral protein R binding protein) axis as an important pathway for p53 regulation. Like Mdm2, VPRBP is a potent repressor of p53 but VPRBP stability is controlled by USP2. Interestingly, the USP2-VPRBP axis also regulates PD-L1 (programmed death-ligand 1) expression. Strikingly, the combination of a small-molecule USP2 inhibitor and anti-PD1 monoclonal antibody leads to complete regression of the tumors expressing wild-type p53. In contrast to Mdm2, knockout of Usp2 in mice has no obvious effect in normal tissues. Moreover, no obvious toxicity is observed upon the USP2 inhibitor treatment in vivo as Mdm2-mediated regulation of p53 remains intact. Our study reveals a promising strategy for p53-based therapy by circumventing the toxicity issue. Nature Publishing Group UK 2023-04-06 /pmc/articles/PMC10079682/ /pubmed/37024504 http://dx.doi.org/10.1038/s41467-023-37617-3 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 Yi, Jingjie Tavana, Omid Li, Huan Wang, Donglai Baer, Richard J. Gu, Wei Targeting USP2 regulation of VPRBP-mediated degradation of p53 and PD-L1 for cancer therapy |
title | Targeting USP2 regulation of VPRBP-mediated degradation of p53 and PD-L1 for cancer therapy |
title_full | Targeting USP2 regulation of VPRBP-mediated degradation of p53 and PD-L1 for cancer therapy |
title_fullStr | Targeting USP2 regulation of VPRBP-mediated degradation of p53 and PD-L1 for cancer therapy |
title_full_unstemmed | Targeting USP2 regulation of VPRBP-mediated degradation of p53 and PD-L1 for cancer therapy |
title_short | Targeting USP2 regulation of VPRBP-mediated degradation of p53 and PD-L1 for cancer therapy |
title_sort | targeting usp2 regulation of vprbp-mediated degradation of p53 and pd-l1 for cancer therapy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10079682/ https://www.ncbi.nlm.nih.gov/pubmed/37024504 http://dx.doi.org/10.1038/s41467-023-37617-3 |
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