The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma.
|Title||The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma.|
|Publication Type||Journal Article|
|Year of Publication||2012|
|Authors||Pérez-Mancera, P. A., A. G. Rust, L. van der Weyden, G. Kristiansen, A. Li, A. L. Sarver, K. A. T. Silverstein, R. Grützmann, D. Aust, P. Rümmele, et al.|
|Corporate Authors||Australian Pancreatic Cancer Genome Initiative, Garvan Institute of Medical Research, Queensland Center for Medical Genomics, Institute for Molecular Bioscience, Royal North Shore Hospital, Bankstown Hospital, Liverpool Hospital, Westmead Hospital, Royal Prince Alfred Hospital, Fremantle Hospital, Sir Charles Gairdner Hospital, St John of God Healthcare, Royal Adelaide Hospital, Flinders Medical Center, Greenslopes Private Hospital, Envoi Pathology, Princess Alexanda Hospital, Austin Hospital, Johns Hopkins Medical Institutes, ARC-NET Center for Applied Research on Cancer, and University of California|
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.