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PXD023424 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleUSP25 is a HIF-1 regulator and a therapeutic target in pancreatic ductal adenocarcinoma
DescriptionPancreatic ductal adenocarcinoma (PDAC) is a devastating disease with both an extremely poor prognosis and response to conventional chemotherapy. Identifying novel biological vulnerabilities is therefore critical in the development of more effective therapies. By using patient-derived organoids and murine genetic models, we developed a pipeline for identifying biologically active deubiquitylases (DUBs) with activity-based proteomics, coupled with a loss-of-function genetic screen in organoids. We found that ubiquitin specific protease 25 (USP25) is indispensable for PDAC progression. Compared with normal pancreatic tissue, USP25 was highly expressed and active in murine PDAC tumours and in primary human PDAC samples. Silencing of Usp25/USP25 led to reduced tumour organoid formation and viability, and transcriptional profiling revealed that USP25 is a regulator of hypoxia, glycolysis and HIF-1 signalling pathways. Mechanistically, we found that USP25 directly interacts with HIF-1 and that its deubiquitylase activity regulates HIF-1 protein stability, nuclear translocation and transcriptional activity. Moreover, treatment with a novel USP25 inhibitor resulted in a dramatic loss of murine and patient-derived organoid viability, HIF-1 signalling, and consequently induced substantial regression of murine and human organoid-derived xenografts in vivo. Thus, USP25 is a promising therapeutic target for the treatment of human PDAC.
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterSteven Howell
SpeciesList scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListiodoacetamide derivatized residue
InstrumentOrbitrap Fusion Lumos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02021-01-06 00:03:43ID requested
12022-05-19 14:17:35announced
Publication List
Nelson JK, Thin MZ, Evan T, Howell S, Wu M, Almeida B, Legrave N, Koenis DS, Koifman G, Sugimoto Y, Llorian Sopena M, MacRae J, Nye E, Howell M, Snijders AP, Prachalias A, Zen Y, Sarker D, Behrens A, USP25 promotes pathological HIF-1-driven metabolic reprogramming and is a potential therapeutic target in pancreatic cancer. Nat Commun, 13(1):2070(2022) [pubmed]
Keyword List
submitter keyword: Human, Mouse, pancreas, cancer, deubiquitylase, biotin, affinity, LC-MSMS
Contact List
James McCrae
contact affiliationActing Head of Proteomics
contact emailJames.MacRae@crick.ac.uk
lab head
Steven Howell
contact affiliationFrancis Crick Institute
contact emailsteven.howell@crick.ac.uk
dataset submitter
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Dataset FTP location
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