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
et al (show 22 more authors) (2021) USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma. ELIFE, 10. e71596-.

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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 <i>Usp28</i>-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.

Item Type: Article
Uncontrolled Keywords: squamous cell lung cancer, USP28, c-MYC, Human
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 24 Jan 2022 10:12
Last Modified: 25 Jan 2024 22:34
DOI: 10.7554/eLife.71596
Open Access URL: https://elifesciences.org/articles/71596
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3147525