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USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma
Lung squamous cell carcinoma (LSCC) is a considerable global health burden, with an incidence of over 600,000 cases per year. Treatment options are limited, and patient’s 5-year survival rate is less than 5%. The ubiquitin-specific protease 28 (USP28) has been implicated in tumourigenesis through it...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8553340/ https://www.ncbi.nlm.nih.gov/pubmed/34636321 http://dx.doi.org/10.7554/eLife.71596 |
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author | Ruiz, E Josue Pinto-Fernandez, Adan Turnbull, Andrew P Lan, Linxiang Charlton, Thomas M Scott, Hannah C Damianou, Andreas Vere, George Riising, Eva M Da Costa, Clive Krajewski, Wojciech W Guerin, David Kearns, Jeffrey D Ioannidis, Stephanos Katz, Marie McKinnon, Crystal O'Connell, Jonathan Moncaut, Natalia Rosewell, Ian Nye, Emma Jones, Neil Heride, Claire Gersch, Malte Wu, Min Dinsmore, Christopher J Hammonds, Tim R Kim, Sunkyu Komander, David Urbe, Sylvie Clague, Michael J Kessler, Benedikt M Behrens, Axel |
author_facet | Ruiz, E Josue Pinto-Fernandez, Adan Turnbull, Andrew P Lan, Linxiang Charlton, Thomas M Scott, Hannah C Damianou, Andreas Vere, George Riising, Eva M Da Costa, Clive Krajewski, Wojciech W Guerin, David Kearns, Jeffrey D Ioannidis, Stephanos Katz, Marie McKinnon, Crystal O'Connell, Jonathan Moncaut, Natalia Rosewell, Ian Nye, Emma Jones, Neil Heride, Claire Gersch, Malte Wu, Min Dinsmore, Christopher J Hammonds, Tim R Kim, Sunkyu Komander, David Urbe, Sylvie Clague, Michael J Kessler, Benedikt M Behrens, Axel |
author_sort | Ruiz, E Josue |
collection | PubMed |
description | Lung squamous cell carcinoma (LSCC) is a considerable global health burden, with an incidence of over 600,000 cases per year. Treatment options are limited, and patient’s 5-year survival rate is less than 5%. The ubiquitin-specific protease 28 (USP28) has been implicated in tumourigenesis through its stabilization of the oncoproteins c-MYC, c-JUN, and Δp63. Here, we show that genetic inactivation of Usp28-induced regression of established murine LSCC lung tumours. We developed a small molecule that inhibits USP28 activity in the low nanomole range. While displaying cross-reactivity against the closest homologue USP25, this inhibitor showed a high degree of selectivity over other deubiquitinases. USP28 inhibitor treatment resulted in a dramatic decrease in c-MYC, c-JUN, and Δp63 proteins levels and consequently induced substantial regression of autochthonous murine LSCC tumours and human LSCC xenografts, thereby phenocopying the effect observed by genetic deletion. Thus, USP28 may represent a promising therapeutic target for the treatment of squamous cell lung carcinoma. |
format | Online Article Text |
id | pubmed-8553340 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-85533402021-10-29 USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma Ruiz, E Josue Pinto-Fernandez, Adan Turnbull, Andrew P Lan, Linxiang Charlton, Thomas M Scott, Hannah C Damianou, Andreas Vere, George Riising, Eva M Da Costa, Clive Krajewski, Wojciech W Guerin, David Kearns, Jeffrey D Ioannidis, Stephanos Katz, Marie McKinnon, Crystal O'Connell, Jonathan Moncaut, Natalia Rosewell, Ian Nye, Emma Jones, Neil Heride, Claire Gersch, Malte Wu, Min Dinsmore, Christopher J Hammonds, Tim R Kim, Sunkyu Komander, David Urbe, Sylvie Clague, Michael J Kessler, Benedikt M Behrens, Axel eLife Biochemistry and Chemical Biology Lung squamous cell carcinoma (LSCC) is a considerable global health burden, with an incidence of over 600,000 cases per year. Treatment options are limited, and patient’s 5-year survival rate is less than 5%. The ubiquitin-specific protease 28 (USP28) has been implicated in tumourigenesis through its stabilization of the oncoproteins c-MYC, c-JUN, and Δp63. Here, we show that genetic inactivation of Usp28-induced regression of established murine LSCC lung tumours. We developed a small molecule that inhibits USP28 activity in the low nanomole range. While displaying cross-reactivity against the closest homologue USP25, this inhibitor showed a high degree of selectivity over other deubiquitinases. USP28 inhibitor treatment resulted in a dramatic decrease in c-MYC, c-JUN, and Δp63 proteins levels and consequently induced substantial regression of autochthonous murine LSCC tumours and human LSCC xenografts, thereby phenocopying the effect observed by genetic deletion. Thus, USP28 may represent a promising therapeutic target for the treatment of squamous cell lung carcinoma. eLife Sciences Publications, Ltd 2021-10-12 /pmc/articles/PMC8553340/ /pubmed/34636321 http://dx.doi.org/10.7554/eLife.71596 Text en © 2021, Ruiz et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Biochemistry and Chemical Biology Ruiz, E Josue Pinto-Fernandez, Adan Turnbull, Andrew P Lan, Linxiang Charlton, Thomas M Scott, Hannah C Damianou, Andreas Vere, George Riising, Eva M Da Costa, Clive Krajewski, Wojciech W Guerin, David Kearns, Jeffrey D Ioannidis, Stephanos Katz, Marie McKinnon, Crystal O'Connell, Jonathan Moncaut, Natalia Rosewell, Ian Nye, Emma Jones, Neil Heride, Claire Gersch, Malte Wu, Min Dinsmore, Christopher J Hammonds, Tim R Kim, Sunkyu Komander, David Urbe, Sylvie Clague, Michael J Kessler, Benedikt M Behrens, Axel USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma |
title | USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma |
title_full | USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma |
title_fullStr | USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma |
title_full_unstemmed | USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma |
title_short | USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma |
title_sort | usp28 deletion and small-molecule inhibition destabilizes c-myc and elicits regression of squamous cell lung carcinoma |
topic | Biochemistry and Chemical Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8553340/ https://www.ncbi.nlm.nih.gov/pubmed/34636321 http://dx.doi.org/10.7554/eLife.71596 |
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