USP28 deletion and small molecule inhibition destabilises 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 Claire, Damianou, Andreas, Vere, George, Riising, Eva M, Da Costa, Clive
et al (show 22 more authors) USP28 deletion and small molecule inhibition destabilises c-Myc and elicits regression of squamous cell lung carcinoma.

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Abstract

<jats:title>Abstract</jats:title><jats:p>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 5-year survival rate is less than 5%. The ubiquitin specific protease 28 (USP28) has been implicated in tumorigenesis through its stabilization of the oncoprotein c-MYC. Here, we show that genetic inactivation of <jats:italic>USP28</jats:italic> induced regression of established murine LSCC lung tumors. We developed a small molecule USP28 inhibitor that interfered with USP28 activity in the low nanomole range. While displaying considerable activity 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 proteins levels and consequently induced substantial regression of autochthonous murine LSCC tumors 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.</jats:p>

Item Type: Article
Depositing User: Symplectic Admin
Date Deposited: 19 Nov 2020 09:07
Last Modified: 13 Jan 2021 18:11
DOI: 10.1101/2020.11.17.377705
Open Access URL: https://www.biorxiv.org/content/10.1101/2020.11.17...
URI: https://livrepository.liverpool.ac.uk/id/eprint/3107424