RT Journal Article
T1 USP28 enables oncogenic transformation of respiratory cells, and its inhibition potentiates molecular therapy targeting mutant EGFR, BRAF and PI3K.
A1 Prieto-Garcia, Cristian
A1 Hartmann, Oliver
A1 Reissland, Michaela
A1 Braun, Fabian
A1 Bozkurt, Süleyman
A1 Pahor, Nikolett
A1 Fuss, Carmina
A1 Schirbel, Andreas
A1 Schülein-Völk, Christina
A1 Buchberger, Alexander
A1 Calzado Canale, Marco A
A1 Rosenfeldt, Mathias
A1 Dikic, Ivan
A1 Münch, Christian
A1 Diefenbacher, Markus E
K1 USP28
K1 Buparlisib
K1 c-MYC
K1 Gefitinib
K1 Lung cancer
K1 Vemurafenib
AB 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.
PB John Wiley & Sons
YR 2022
FD 2022-03-29
LK http://hdl.handle.net/10668/19619
UL http://hdl.handle.net/10668/19619
LA en
NO Prieto-Garcia C, Hartmann O, Reissland M, Braun F, Bozkurt S, Pahor N, et al. USP28 enables oncogenic transformation of respiratory cells, and its inhibition potentiates molecular therapy targeting mutant EGFR, BRAF and PI3K. Mol Oncol. 2022 Sep;16(17):3082-3106
NO We are grateful to the animal facility and Barbara Bauer at the Biocenter, University of Wurzburg. CP-G € and OH are supported by the German Cancer Aid via grant 70112491 and 70114554. MR is funded by the DFG-GRK 2243 and IZKF B335. MED and MR are funded by the German Israeli Foundation grant 1431.Open Access funding enabled and organized by ProjektDEAL
DS RISalud
RD Apr 6, 2025