USP28 enables oncogenic transformation of respiratory cells, and its inhibition potentiates molecular therapy targeting mutant EGFR, BRAF and PI3K

  • Oncogenic transformation of lung epithelial cells is a multistep process, frequently starting with the inactivation of tumour suppressors and subsequent development of activating mutations in proto-oncogenes, such as members of the PI3K or MAPK families. Cells undergoing transformation have to adjust to changes, including altered metabolic requirements. This is achieved, in part, by modulating the protein abundance of transcription factors. Here, we report that the ubiquitin carboxyl-terminal hydrolase 28 (USP28) enables oncogenic reprogramming by regulating the protein abundance of proto-oncogenes such as c-JUN, c-MYC, NOTCH and ∆NP63 at early stages of malignant transformation. USP28 levels are increased in cancer compared with in normal cells due to a feed-forward loop, driven by increased amounts of oncogenic transcription factors such as c-MYC and c-JUN. Irrespective of oncogenic driver, interference with USP28 abundance or activity suppresses growth and survival of transformed lung cells. Furthermore, inhibition of USP28 via a small-molecule inhibitor resets the proteome of transformed cells towards a ‘premalignant’ state, and its inhibition synergizes with clinically established compounds used to target EGFRL858R-, BRAFV600E- or PI3KH1047R-driven tumour cells. Targeting USP28 protein abundance at an early stage via inhibition of its activity is therefore a feasible strategy for the treatment of early-stage lung tumours, and the observed synergism with current standard-of-care inhibitors holds the potential for improved targeting of established tumours.

Download full text files

Export metadata

Metadaten
Author:Cristian Prieto GarcíaORCiDGND, Oliver HartmannORCiDGND, Michaela ReisslandORCiD, Fabian Braun, Süleyman BozkurtORCiD, Nikolett Pahor, Carmina Teresa FußORCiDGND, Andreas SchirbelGND, Christina SchüleinORCiDGND, Alexander BuchbergerORCiDGND, Marco A. Calzado CanaleORCiD, Mathias Tillmann RosenfeldtORCiDGND, Ivan ĐikićORCiDGND, Christian MünchORCiDGND, Markus Elmar DiefenbacherORCiD
URN:urn:nbn:de:hebis:30:3-855741
DOI:https://doi.org/10.1002/1878-0261.13217
ISSN:1878-0261
Parent Title (English):Molecular Oncology
Publisher:John Wiley & Sons, Inc.
Place of publication:Hoboken, NJ
Document Type:Article
Language:English
Date of Publication (online):2022/04/01
Date of first Publication:2022/04/01
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2024/06/04
Tag:USP28; buparlisib; c-MYC; gefitinib; lung cancer; vemurafenib
Volume:16
Issue:17
Page Number:25
First Page:3082
Last Page:3106
Note:
Open Access funding enabled and organized by Projekt DEAL.
Note:
Funding: Interdisziplinäres Zentrum für Klinische Forschung ; B335, Z2/CS-1
Note:
Funding: Deutsche Forschungsgemeinschaft ; GRK2243
Note:
Funding: German-Israeli Foundation for Scientific Research and Development ; 1431
Note:
Funding: Deutsche Krebshilfe ; 70112491
Note:
Funding: Deutsche Krebshilfe ; 70114554
HeBIS-PPN:520894464
Institutes:Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International