PXD032810-1

PXD032810 is an original dataset announced via ProteomeXchange.

Title	USP28 enables oncogenic transformation of respiratory cells and its inhibition potentiates molecular therapy targeting mutant EGFR, BRAF and PI3K.
Description	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 ∆NP63, 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.
HostingRepository	PRIDE
AnnounceDate	2022-04-08
AnnouncementXML	Submission_2022-04-08_03:44:49.395.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Süleyman Bozkurt
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-03-25 05:13:47	ID requested
⏵ 1	2022-04-08 03:44:50	announced

Prieto-Garcia C, Hartmann O, Reissland M, Braun F, Bozkurt S, Pahor N, Fuss C, Schirbel A, Sch, ü, lein-V, ö, lk C, Buchberger A, Calzado Canale MA, Rosenfeldt M, Dikic I, M, ü, nch C, Diefenbacher ME, USP28 enables oncogenic transformation of respiratory cells, and its inhibition potentiates molecular therapy targeting mutant EGFR, BRAF and PI3K. Mol Oncol, 16(17):3082-3106(2022) [pubmed]

submitter keyword: USP28, c-MYC, c-JUN, lung cancer, EGFR, PIK3CA, BRAF, HRAS Gefitinib, Buparlisib, Vemurafenib

Christian Münch
contact affiliation	Institute of Biochemistry II, Faculty of Medicine, Goethe University, Frankfurt am Main, Germany Frankfurt Cancer Institute, Frankfurt am Main, Germany Cardio-Pulmonary Institute, Frankfurt am Main, Germany
contact email	ch.muench@em.uni-frankfurt.de
lab head
Süleyman Bozkurt
contact affiliation	Institute of Biochemistry II, Goethe University Frankfurt, Theodor-Stern-Kai 7, Haus 75 60590 Frankfurt am Main
contact email	bozkurt@med.uni-frankfurt.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2022/04/PXD032810

PRIDE project URI

• PRIDE
  1. PXD032810
     1. Label: PRIDE project
     2. Name: USP28 enables oncogenic transformation of respiratory cells and its inhibition potentiates molecular therapy targeting mutant EGFR, BRAF and PI3K.