TY  - INPR
A1  - Prieto García, Cristian
A1  - Hartmann, Oliver
A1  - Reissland, Michaela
A1  - Braun, Fabian
A1  - Bozkurt, Süleyman
A1  - Fuß, Carmina Teresa
A1  - Schülein-Völk, 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  - bioRxiv
N2  - Oncogenic transformation of lung epithelial cells is a multi-step process, frequently starting with the inactivation of tumor suppressors and subsequent activating mutations in proto-oncogenes, such as members of the PI3K or MAPK family. Cells undergoing transformation have to adjust to changes, such as metabolic requirements. This is achieved, in part, by modulating the protein abundance of transcription factors, which manifest these adjustments. Here, we report that the deubiquitylase USP28 enables oncogenic reprogramming by regulating the protein abundance of proto-oncogenes, such as c-JUN, c-MYC, NOTCH and ΔNP63, at early stages of malignant transformation. USP28 is increased in cancer compared to 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 reset the proteome of transformed cells towards a ‘pre-malignant’ state, and its inhibition cooperated with clinically established compounds used to target EGFRL858R, BRAFV600E or PI3KH1047R driven tumor cells. Targeting USP28 protein abundance already at an early stage via inhibition of its activity therefore is 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 tumors.
KW  - USP28
KW  - c-MYC
KW  - c-JUN
KW  - lung cancer
KW  - EGFR
KW  - PIK3CA
KW  - BRAF
KW  - HRAS 28 Gefitinib
KW  - Buparlisib
KW  - Vemurafenib
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/72932
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-729326
UR  - https://www.biorxiv.org/content/10.1101/2021.09.06.459088v1
IS  - 2021.09.06.459088 Version 1
PB  - bioRxiv
ER  -