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 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.

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Author:Cristian Prieto GarcíaORCiDGND, Oliver HartmannORCiDGND, Michaela ReisslandORCiD, Fabian Braun, Süleyman BozkurtORCiD, Carmina Teresa FußORCiDGND, Christina Schülein-VölkORCiDGND, Alexander BuchbergerORCiDGND, Marco A. Calzado CanaleORCiD, Mathias Tillmann RosenfeldtORCiDGND, Ivan ĐikićORCiDGND, Christian MünchORCiDGND, Markus Elmar DiefenbacherORCiD
URN:urn:nbn:de:hebis:30:3-729326
URL:https://www.biorxiv.org/content/10.1101/2021.09.06.459088v1
DOI:https://doi.org/10.1101/2021.09.06.459088
Parent Title (English):bioRxiv
Publisher:bioRxiv
Document Type:Preprint
Language:English
Date of Publication (online):2021/09/06
Date of first Publication:2021/09/06
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2024/06/13
Tag:BRAF; Buparlisib; EGFR; HRAS 28 Gefitinib; PIK3CA; USP28; Vemurafenib; c-JUN; c-MYC; lung cancer
Issue:2021.09.06.459088 Version 1
Edition:Version 1
Page Number:39
HeBIS-PPN:519860365
Institutes:Biochemie, Chemie und Pharmazie / Biochemie und Chemie
Fachübergreifende Einrichtungen / Buchmann Institut für Molekulare Lebenswissenschaften (BMLS)
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International