The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma.
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.
Li Ka Shing Centre, Cambridge Research Institute, Cancer Research UK, Cambridge CB2 0RE, UK.
Pedro A
PA
Pérez-Mancera
Alistair G
AG
Rust
Louise
L
van der Weyden
Glen
G
Kristiansen
Allen
A
Li
Aaron L
AL
Sarver
Kevin A T
KA
Silverstein
Robert
R
Grützmann
Daniela
D
Aust
Petra
P
Rümmele
Thomas
T
Knösel
Colin
C
Herd
Derek L
DL
Stemple
Ross
R
Kettleborough
Jacqueline A
JA
Brosnan
Ang
A
Li
Richard
R
Morgan
Spencer
S
Knight
Jun
J
Yu
Shane
S
Stegeman
Lara S
LS
Collier
Jelle J
JJ
ten Hoeve
Jeroen
J
de Ridder
Alison P
AP
Klein
Michael
M
Goggins
Ralph H
RH
Hruban
David K
DK
Chang
Andrew V
AV
Biankin
Sean M
SM
Grimmond
Lodewyk F A
LF
Wessels
Stephen A
SA
Wood
Christine A
CA
Iacobuzio-Donahue
Christian
C
Pilarsky
David A
DA
Largaespada
David J
DJ
Adams
David A
DA
Tuveson
D000818:Animals; D023102:Anoikis / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D010450:Endopeptidases; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D020298:U937 Cells; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism*
C506234:USP9X protein, human; D010450:Endopeptidases; D043222:Ubiquitin Thiolesterase; C404328:Usp9x protein, mouse