| Title: |
The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma |
| Authors: |
Perez-Mancera, P; Rust, AG; van der Weyden, L; Kristiansen, GO; Li, A; Sarver, AL; Silverstein, KAT; Grutzmann, R; Aust, DE; Rummele, P; Knosel, T; Herd, C; Stemple, D; Kettleborough, R; Brosnan, JA; Richard, G Morgan; Knight, S; Yu, J; Stegeman, S; Collier, LS; Ten Hoeve, JJ; De Ridder, J; Klein, A; Goggins, M; Hruban, R; Chang, D; Biankin, AV; Pinese, M; Grimmond, S; Wessels, L; Wood, S; Iacobuzio-donahue, CA; Pilarsky, CP; Largaespada, DA; Adams, DJ; Tuveson, DA; Rooman, Ilse; Pavey, Darren; Cosman, Peter; Nagrial, Adnan; Merrett, Neil; asghari, Ray; Cowley, Mark; Daly, Roger; Musgrove, Elizabeth; Pajic, Marina; Wu, Jianmin; Chang, David; Chantrill, Lorraine; Sutherland, Robert; Gill, Anthony; Mawson, Amanda; Chou, Angela; Kaplan, Warren; Toon, Christopher Chien Wei; Johns, Amber |
| Source: |
urn:ISSN:0028-0836 ; urn:ISSN:1476-4687 ; Nature, 486, 7402, 266-270 |
| Publisher Information: |
Nature Publishing Group |
| Publication Year: |
2012 |
| Collection: |
UNSW Sydney (The University of New South Wales): UNSWorks |
| Subject Terms: |
32 Biomedical and Clinical Sciences; 3211 Oncology and Carcinogenesis; Rare Diseases; Cancer; Genetics; Digestive Diseases; Orphan Drug; Pancreatic Cancer; Animals; Anoikis; Carcinoma; Pancreatic Ductal; Cell Line; Tumor; Disease Models; Animal; Endopeptidases; Gene Expression Regulation; Neoplastic; Gene Knockdown Techniques; Humans; Mice; Inbred C57BL; Pancreatic Neoplasms; U937 Cells; Ubiquitin Thiolesterase; Australian Pancreatic Cancer Genome Initiative; anzsrc-for: 32 Biomedical and Clinical Sciences; anzsrc-for: 3211 Oncology and Carcinogenesis; anzsrc-for: 110399 Clinical Sciences not elsewhere classified |
| Description: |
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-2Œ-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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
https://hdl.handle.net/1959.4/unsworks_67418; https://doi.org/10.1038/nature11114 |
| DOI: |
10.1038/nature11114 |
| Availability: |
https://hdl.handle.net/1959.4/unsworks_67418; https://unsworks.unsw.edu.au/bitstreams/9d485dff-e69f-4041-a409-266ab8750d1c/download; https://doi.org/10.1038/nature11114 |
| Rights: |
open access ; https://purl.org/coar/access_right/c_abf2 ; CC-BY-NC-ND ; https://creativecommons.org/licenses/by-nc-nd/4.0/ ; free_to_read |
| Accession Number: |
edsbas.C4D6B3AA |
| Database: |
BASE |