학술논문
USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma
Document Type
article
Author
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
Source
eLife, Vol 10 (2021)
Subject
Language
English
ISSN
2050-084X
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.