The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma.
| Title: | The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma. |
|---|---|
| Authors: | Pérez-Mancera PA; Rust AG; van der Weyden L; Kristiansen G; Li A; Sarver AL; Silverstein KA; Grützmann R; Aust D; Rümmele P; Knösel T; Herd C; Stemple DL; Kettleborough R; Brosnan JA; Morgan R; Knight S; Yu J; Stegeman S; Collier LS; ten Hoeve JJ; de Ridder J; Klein AP; Goggins M; Hruban RH; Chang DK; Biankin AV; Grimmond SM; Australian Pancreatic Cancer Genome Initiative; Wessels LF; Wood SA; Iacobuzio-Donahue CA; Pilarsky C; Largaespada DA; Adams DJ; Tuveson DA; Collaborators Australian Pancreatic Cancer Genome Initiative: Andrew V Biankin; Amber L Johns; Amanda Mawson; David K Chang; Mary-Anne L Brancato; Sarah J Rowe; Skye L Simpson; Mona Martyn-Smith; Lorraine A Chantrill; Venessa T Chin; Angela Chou; Mark J Cowley; Jeremy L Humphris; Marc D Jones; R Scott Mead; Adnan M Nagrial; Marina Pajic; Jessica Pettit; Mark Pinese; Ilse Rooman; Jianmin Wu; Roger J Daly; Elizabeth A Musgrove; Robert L Sutherland; Sean M Grimmond; Nicola Waddell; Karin S Kassahn; David K Miller; Peter J Wilson; Ann-Marie Patch; Sarah Song; Ivon Harliwong; Senel Idrisoglu; Craig Nourse; Ehsan Nourbakhsh; Suzanne Manning; Shivangi Wani; Milena Gongora; Matthew Anderson; Oliver Holmes; Conrad Leonard; Darrin Taylor; Scott Wood; Christina Xu; Katia Nones; J Lynn Fink; Angelika Christ; Tim Bruxner; Nicole Cloonan; Felicity Newell; John V Pearson; Jaswinder S Samra; Anthony J Gill; Nick Pavlakis; Alex Guminski; Christopher Toon; Andrew V Blankin; Ray Asghari; Neil D Merrett; Darren A Pavey; Amitabha Das; Peter H Cosman; Kasim Ismail; Chelsie O'Connor; Vincent W Lam; Duncan McLeod; Henry C Pleass; Virginia James; James G Kench; Caroline L Cooper; David Joseph; Charbel Sandroussi; Laycock Crawford; Michael Texler; Cindy Forrest; Andrew Laycock; Krishna P Epari; Mo Ballal; David R Fletcher; Sanjay Mukhedkar; Nigel A Spry; Bastiaan DeBoer; Ming Chai; Kynan Feeney; Nikolajs Zeps; Maria Beilin; Nam Q Nguyen; Andrew R Ruszkiewicz; Chris Worthley; Chuan P Tan; Tamara Debrencini; John Chen; Mark E Brooke-Smith; Virginia Papangelis; Henry Tang; Andrew P Barbour; Andrew D Clouston; Patrick Martin; Thomas J O'Rourke; Amy Chiang; Jonathan W Fawcet; Kellee Slater; Shinn Yeung; Michael Hatzifotis; Peter Hodgkinson; Christopher Christophi; Mehrdad Nikfarjam; James R Eshleman; Ralph H Hruban; Anirban Maitra; Christine A Iacobuzio-Donahue; Richard D Schulick; Christopher L Wolfgang; Richard A Morgan; Rita T Lawlor; Stefania Beghelli; Vincenzo Corbo; Maria Scardoni; Claudio Bassi; Margaret A Tempero; Christopher J Scarlett; Warren Kaplan; Aldo Scarpa |
| Contributors: | Pa, Pérez-Mancera; Ag, Rust; L, van der Weyden; G, Kristiansen; A, Li; Al, Sarver; Ka, Silverstein; R, Grützmann; D, Aust; P, Rümmele; T, Knösel; C, Herd; Dl, Stemple; R, Kettleborough; Ja, Brosnan; R, Morgan; S, Knight; J, Yu; S, Stegeman; Ls, Collier; Hoeve JJ, Ten; J, de Ridder; Ap, Klein; M, Goggin; Rh, Hruban; Dk, Chang; Av, Biankin; Sm, Grimmond; Pancreatic Cancer Genome Initiative, Australian; Lf, Wessel; Sa, Wood; Ca, Iacobuzio-Donahue; C, Pilarsky; Da, Largaespada; Dj, Adam; Da, Tuveson; V Biankin, Collaborators Australian Pancreatic Cancer Genome Initiative: Andrew; L Johns, Amber; Mawson, Amanda; K Chang, David; L Brancato, Mary-Anne; J Rowe, Sarah; L Simpson, Skye; Martyn-Smith, Mona; A Chantrill, Lorraine; T Chin, Venessa; Chou, Angela; J Cowley, Mark; L Humphris, Jeremy; D Jones, Marc; Scott Mead, R; M Nagrial, Adnan; Pajic, Marina; Pettit, Jessica; Pinese, Mark; Rooman, Ilse; Wu, Jianmin; J Daly, Roger; A Musgrove, Elizabeth; L Sutherland, Robert; M Grimmond, Sean; Waddell, Nicola; S Kassahn, Karin; K Miller, David; J Wilson, Peter; Patch, Ann-Marie; Song, Sarah; Harliwong, Ivon; Idrisoglu, Senel; Nourse, Craig; Nourbakhsh, Ehsan; Manning, Suzanne; Wani, Shivangi; Gongora, Milena; Anderson, Matthew; Holmes, Oliver; Leonard, Conrad; Taylor, Darrin; Wood, Scott; Xu, Christina; Nones, Katia; Lynn Fink, J; Christ, Angelika; Bruxner, Tim; Cloonan, Nicole; Newell, Felicity; V Pearson, John; S Samra, Jaswinder; J Gill, Anthony; Pavlakis, Nick; Guminski, Alex; Toon, Christopher; V Blankin, Andrew; Asghari, Ray; D Merrett, Neil; A Pavey, Darren; Das, Amitabha; H Cosman, Peter |
| Publication Year: | 2012 |
| Collection: | Università degli Studi di Verona: Catalogo dei Prodotti della Ricerca (IRIS) |
| Subject Terms: | SOMATIC MUTATIONS; INSERTION SITES; K-RAS; GENE; CANCER; MOUSE; MUTAGENESIS; CARCINOMA; EXPRESSION; STABILIZATION |
| Description: | Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations in addition to numerous lower frequency genetic events of uncertain significance. Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis in a mouse model of pancreatic ductal preneoplasia to identify genes that cooperate with oncogenic Kras(G12D) 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 neoplasia, 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 Kras(G12D) 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. |
| Document Type: | article in journal/newspaper |
| Language: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/22699621; info:eu-repo/semantics/altIdentifier/wos/WOS:000305189000037; volume:486; issue:7402; firstpage:266; lastpage:270; numberofpages:4; journal:NATURE; https://hdl.handle.net/11562/431407; http://dx.doi.org/10.1038/nature11114 |
| DOI: | 10.1038/nature11114 |
| Availability: | https://hdl.handle.net/11562/431407; https://doi.org/10.1038/nature11114 |
| Accession Number: | edsbas.605DBD06 |
| Database: | BASE |