EJ Ruiz
USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma
Ruiz, EJ; Pinto-Fernandez, A; Turnbull, AP; Lan, LX; 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
Authors
A Pinto-Fernandez
AP Turnbull
LX Lan
TM Charlton
HC Scott
A Damianou
G Vere
EM Riising
C Da Costa
WW Krajewski
D Guerin
JD Kearns
S Ioannidis
M Katz
C McKinnon
J O'Connell
N Moncaut
I Rosewell
E Nye
N Jones
C Heride
M Gersch
M Wu
CJ Dinsmore
TR Hammonds
S Kim
D Komander
S Urbe
MJ Clague
BM Kessler
A Behrens
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 Delta p63. 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 Delta p63 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.
Citation
Ruiz, E., Pinto-Fernandez, A., Turnbull, A., Lan, L., Charlton, T., Scott, H., …Behrens, A. (2021). USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma. eLife, 10, https://doi.org/10.7554/eLife.71596%3B+10.7554/eLife.71596.sa1%3B+10.7554/eLife.71596.sa2
Journal Article Type | Article |
---|---|
Acceptance Date | Oct 10, 2021 |
Publication Date | 2021 |
Deposit Date | Jan 12, 2022 |
Publicly Available Date | Jan 12, 2022 |
Publisher | eLife Sciences Publications |
Peer Reviewed | Peer Reviewed |
Volume | 10 |
DOI | https://doi.org/10.7554/eLife.71596%3B+10.7554/eLife.71596.sa1%3B+10.7554/eLife.71596.sa2 |
Keywords | squamous cell lung cancer; USP28; c-MYC; Human; INTESTINAL HOMEOSTASIS; CHEMOTHERAPY; CANCER; FBW7; CISPLATIN; GENOMICS; SYSTEM |
Public URL | https://rvc-repository.worktribe.com/output/1555522 |
Files
OA
(4.3 Mb)
PDF
Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/
Downloadable Citations
About RVC Repository
Administrator e-mail: publicationsrepos@rvc.ac.uk
This application uses the following open-source libraries:
SheetJS Community Edition
Apache License Version 2.0 (http://www.apache.org/licenses/)
PDF.js
Apache License Version 2.0 (http://www.apache.org/licenses/)
Font Awesome
SIL OFL 1.1 (http://scripts.sil.org/OFL)
MIT License (http://opensource.org/licenses/mit-license.html)
CC BY 3.0 ( http://creativecommons.org/licenses/by/3.0/)
Powered by Worktribe © 2024
Advanced Search