The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma

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Title The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma
Author Pérez-Mancera, Pedro A.; Rust, Alistair G.; Weyden, Louise van der; Kristiansen, Glen; Li, Allen; Sarver, Aaron L.; Silverstein, Kevin A. T.; Grutzmann, Robert; Aust, Daniela; Rummele, Petra; Knosel, Thomas; Herd, Colin; Stemple, Derek L.; Kettleborough, Ross; Brosnan, Jacqueline A.; Li, Ang; Morgan, Richard; Knight, Spencer; Yu, Jun; Stegeman, Shane; Collier, Lara S.; Hoeve, Jelle J. ten; Ridder, Jeroen de; Klein, Alison P.; Goggins, Michael; Hruban, Ralph H.; Chang, David K.; Biankin, Andrew V.; Wood, Stephen Andrew; al, et
Journal Name Nature
Year Published 2012
Place of publication United Kingdom
Publisher Nature Publishing Group
Abstract Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations1, 2, 3, 4 in addition to numerous lower frequency genetic events of uncertain significance5. Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis6, 7 in a mouse model of pancreatic ductal preneoplasia8 to identify genes that cooperate with oncogenic KrasG12D to accelerate tumorigenesis and promote progression. Our screen revealed new candidate genes for PDA and confirmed the importance of many genes and pathways previously implicated in human PDA. The most commonly mutated gene was the X-linked deubiquitinase Usp9x, which was inactivated in over 50% of the tumours. Although previous work had attributed a pro-survival role to USP9X in human neoplasia9, we found instead that loss of Usp9x enhances transformation and protects pancreatic cancer cells from anoikis. Clinically, low USP9X protein and messenger RNA expression in PDA correlates with poor survival after surgery, and USP9X levels are inversely associated with metastatic burden in advanced disease. Furthermore, chromatin modulation with trichostatin A or 5-aza-2′-deoxycytidine elevates USP9X expression in human PDA cell lines, indicating a clinical approach for certain patients. The conditional deletion of Usp9x cooperated with KrasG12D to accelerate pancreatic tumorigenesis in mice, validating their genetic interaction. We propose that USP9X is a major tumour suppressor gene with prognostic and therapeutic relevance in PDA.
Peer Reviewed Yes
Published Yes
Alternative URI http://dx.doi.org/10.1038/nature11114
Volume 486
Issue Number 7402
Page from 266
Page to 270
ISSN 0028-0836
Date Accessioned 2012-05-25
Date Available 2014-08-28T22:16:51Z
Language en_US
Research Centre Eskitis Institute for Drug Discovery
Faculty Faculty of Science, Environment, Engineering and Technology
Subject Molecular Targets
URI http://hdl.handle.net/10072/46995
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1

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