USP28 deletion and small molecule inhibition destabilises c-MYC and elicits regression of squamous cell lung carcinoma
- Author(s)
- Ruiz, EJ; Pinto-Fernandez, A; Turnbull, AP; Lan, L; Charlton, TM; Scott, HC; Damianou, A; Vere, G; Riising, EM; Da Costa, C; Krajewski, WW; Guerin, D; Kearns, JD; Ioannidis, S; Katz, M; McKinnon, C; O'Connell, J; Moncaut, N; Rosewell, I; Nye, E; Jones, N; Heride, C; Gersch, M; Wu, M; Dinsmore, CJ; Hammonds, TR; Kim, S; Komander, D; Urbe, S; Clague, MJ; Kessler, BM; Behrens, A;
- Journal Title
- eLife
- 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 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.
- Publisher
- eLife Sciences
- Keywords
- biochemistry; cancer biology; chemical biology; human; c-Mer Tyrosine Kinase/*antagonists & inhibitors/*biosynthesis
- Research Division(s)
- Ubiquitin Signalling
- PubMed ID
- 34636321
- Publisher's Version
- https://doi.org/10.7554/eLife.71596
- Open Access at Publisher's Site
https://doi.org/10.7554/eLife.71596- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2021-10-26 10:04:00
Last Modified: 2021-10-29 09:26:59