USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma.
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ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2021-10-12
Date Accepted
2021-10-10
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.
Citation
eLife, 2021, 10
Source Title
Publisher
eLIFE SCIENCES PUBL LTD
ISSN
2050-084X
eISSN
2050-084X