USP28 deletion and small molecule inhibition destabilises c-MYC and elicits regression of squamous cell lung carcinoma.
journal contributionposted on 2021-11-03, 12:33 authored by E Josue Ruiz, Adan Pinto-Fernandez, Andrew P Turnbull, Linxiang Lan, Thomas M Charlton, Hannah Claire 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 C 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 Urbé, Michael J Clague, Benedikt M Kessler, Axel Behrens
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 oncoproteins c-MYC, c-JUN and Dp63. 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 Dp63 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.