1. USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma
- Author
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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, and Axel Behrens
- Subjects
squamous cell lung cancer ,USP28 ,c-MYC ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
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.
- Published
- 2021
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