TY  - JOUR
A1  - Prieto García, Cristian
A1  - Hartmann, Oliver
A1  - Reissland, Michaela
A1  - Braun, Fabian
A1  - Bozkurt, Süleyman
A1  - Pahor, Nikolett
A1  - Fuß, Carmina Teresa
A1  - Schirbel, Andreas
A1  - Schülein, Christina
A1  - Buchberger, Alexander
A1  - Calzado Canale, Marco A.
A1  - Rosenfeldt, Mathias Tillmann
A1  - Đikić, Ivan
A1  - Münch, Christian
A1  - Diefenbacher, Markus Elmar
T1  - USP28 enables oncogenic transformation of respiratory cells, and its inhibition potentiates molecular therapy targeting mutant EGFR, BRAF and PI3K
T2  - Molecular Oncology
N2  - 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.
KW  - buparlisib
KW  - c-MYC
KW  - gefitinib
KW  - lung cancer
KW  - USP28
KW  - vemurafenib
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/85574
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-855741
SN  - 1878-0261
N1  - Open Access funding enabled and organized by Projekt DEAL.
N1  - Funding: Interdisziplinäres Zentrum für Klinische Forschung ; B335, Z2/CS-1
N1  - Funding: Deutsche Forschungsgemeinschaft ; GRK2243
N1  - Funding: German-Israeli Foundation for Scientific Research and Development ; 1431
N1  - Funding: Deutsche Krebshilfe ; 70112491
N1  - Funding: Deutsche Krebshilfe ; 70114554
VL  - 16
IS  - 17
SP  - 3082
EP  - 3106
PB  - John Wiley & Sons, Inc.
CY  - Hoboken, NJ
ER  -