PXD040496 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Deubiquitinase USP9X loss sensitizes renal cancer cells to mTOR inhibition |
Description | mTOR is a central regulator of mammalian metabolism and physiology. Aberrant hyperactivation of this pathway promotes tumor growth and metastasis and drives tumor resistance to chemotherapy and cancer drugs, making mTOR an attractive cancer therapeutic target. mTOR inhibitors have been approved to treat cancer, however, the basis for drug sensitivity remains poorly understood. Here, whole exome sequencing of three chromophobe renal cell carcinoma (chRCC) patients with exceptional mTOR inhibitor sensitivity, uncovered USP9X deubiquitinase as the only mutated gene shared by the tumors. The clonal characteristics of the mutations, revealed by studying multiple patients’ primary and metastatic samples along the years, together with the low USP9X mutation rate in unselected chRCC series, reinforced a causal link between USP9X and mTOR inhibitor sensitivity. Rapamycin treatment of USP9X depleted HeLa and renal cancer 786-O cells and the pharmacological inhibition of USP9X, confirmed a crucial role of this protein in the patients’ sensitivity to mTOR inhibition. As no direct effect of USP9X in mTORC1 was detected, we performed ubiquitylome analyses that identified p62 as a direct USP9X target. Increased p62 ubiquitination and an augmented rapamycin effect upon bortezomib treatment, together with p62 and LC3 immunofluorescence assays, suggested that dysregulated autophagy in USP9X depleted cells can synergize with mTOR inhibitors. In summary, here we show that USP9X constitutes a potential novel marker of sensitivity to mTOR inhibitors in chRCC patients and represents a clinically exploitable strategy that could increase sensitivity to these drugs |
HostingRepository | PRIDE |
AnnounceDate | 2024-10-22 |
AnnouncementXML | Submission_2024-10-22_05:48:14.258.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Fernando Garcia |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | ubiquitination signature tetrapeptidyl lysine |
Instrument | Q Exactive |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2023-02-28 03:43:22 | ID requested | |
1 | 2023-06-14 05:33:52 | announced | |
2 | 2023-11-14 09:00:44 | announced | 2023-11-14: Updated project metadata. |
⏵ 3 | 2024-10-22 05:48:15 | announced | 2024-10-22: Updated project metadata. |
Publication List
Rold, á, n-Romero JM, Valdivia C, Santos M, Lanillos J, Maroto P, Anguera G, Calsina B, Martinez-Montes A, Monteagudo M, Mellid S, Leandro-Garc, í, a LJ, Montero-Conde C, Casc, ó, n A, Roncador G, Coloma J, Robledo M, Rodriguez-Antona C, Deubiquitinase USP9X loss sensitizes renal cancer cells to mTOR inhibition. Int J Cancer, 153(6):1300-1312(2023) [pubmed] |
10.1002/ijc.34575; |
Keyword List
submitter keyword: ubiquitinase,USP9x, human, renal cancer, mTOR |
Contact List
Fernando Garcia |
contact affiliation | Proteomics & MS Specialist Proteomics Unit, Spanish National Cancer Research Centre (CNIO) Melchor Fernández Almagro 3. E28029 MADRID, SPAIN. Phone +34 912246900 ext 3112 |
contact email | fgarcia@cnio.es |
lab head | |
Fernando Garcia |
contact affiliation | Fernando García Martínez, Ph.D. Proteomics Unit, Spanish National cancer Research Center, CNIO, MADRID, SPAIN |
contact email | fgarcia@cnio.es |
dataset submitter | |
Full Dataset Link List
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/2023/06/PXD040496 |
PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD040496
- Label: PRIDE project
- Name: Deubiquitinase USP9X loss sensitizes renal cancer cells to mTOR inhibition