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USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma

التفاصيل البيبلوغرافية
العنوان: USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma
المؤلفون: E Josue Ruiz, Adan Pinto-Fernandez, Andrew P Turnbull, Linxiang Lan, Thomas M Charlton, Hannah C Scott, Andreas Damianou, George Vere, Eva M Riising, Clive Da Costa, Wojciech W Krajewski, David Guerin, Jeffrey D Kearns, Stephanos Ioannidis, Marie Katz, Crystal McKinnon, Jonathan O'Connell, Natalia Moncaut, Ian Rosewell, Emma Nye, Neil Jones, Claire Heride, Malte Gersch, Min Wu, Christopher J Dinsmore, Tim R Hammonds, Sunkyu Kim, David Komander, Sylvie Urbe, Michael J Clague, Benedikt M Kessler, Axel Behrens
المصدر: eLife, Vol 10 (2021)
بيانات النشر: eLife Sciences Publications Ltd, 2021.
سنة النشر: 2021
المجموعة: LCC:Medicine
LCC:Science
LCC:Biology (General)
مصطلحات موضوعية: squamous cell lung cancer, USP28, c-MYC, Medicine, Science, Biology (General), QH301-705.5
الوصف: 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.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 2050-084X
Relation: https://elifesciences.org/articles/71596; https://doaj.org/toc/2050-084X
DOI: 10.7554/eLife.71596
URL الوصول: https://doaj.org/article/eeea231092ca40e880a44f8ed5d20d8d
رقم الأكسشن: edsdoj.231092ca40e880a44f8ed5d20d8d
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:2050084X
DOI:10.7554/eLife.71596