The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite tremendous progress in its molecular characterization. Indeed, PDA tumors harbor four signature somatic mutations1–4, and a plethora of lower frequency genetic events of uncertain significance5. Here, we used 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 candidates and confirmed the importance of many genes and pathways previously implicated in human PDA. Interestingly, the most commonly mutated gene was the X-linked deubiquitinase Usp9x, which was inactivated in over 50% of the tumors. Although prior 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 mRNA expression in PDA correlates with poor survival following 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 to suggest a clinical approach for certain patients. The conditional deletion of Usp9x cooperated with KrasG12D to rapidly accelerate pancreatic tumorigenesis in mice, validating their genetic interaction. Therefore, we propose USP9X as a major new tumor suppressor gene with prognostic and therapeutic relevance in PDA.

Regulation of T cell function by the ubiquitin-specific protease USP9X via modulating the Carma1-Bcl10-Malt1 complex

“…Previous studies have demonstrated that USP9X has different target substrates in different cell types. One study showed that USP9X promotes cell survival by stabilizing Mcl1 in a deubiquitination-dependent manner in human lymphoma (20), whereas a more recent report showed that USP9X expression is inversely linked with pancreatic cancer by acting as a tumor suppressor (21). It seems that USP9X does not play a role in T-cell survival, as revealed in the present study.…”

“…Recent studies have reported that USP9X plays important role in the regulation of cell survival and TGF-β signaling by deubiquitinating myeloid leukemia cell differentiation protein 1 (Mcl1), Itch, and Smad4 (20)(21)(22); however, the function of USP9X in the immune system, particularly in T-cell regulation, remains unknown. In this study, we identified USP9X as a critical positive regulator of TCR signaling pathway and characterized the function of USP9X by genetic, molecular, and immunologic studies.…”

Beclin 1 restrains tumorigenesis through Mcl-1 destabilization in an autophagy-independent reciprocal manner

“…Indeed, recent reports suggest both tumour promoting as well as tumour suppressive functions for USP9X in different contexts 7,37 . It will be relevant in the future to identify the factors that dictate the positive or negative contribution of USP9X to tumorigenesis, and govern its substrate specificity and recruitment, and to study how its cellular distribution may regulate its availability for interacting proteins.…”

Cancer of mice and men: old twists and new tails

“…There is a strong overlap between the orthologues of genes identified in mouse insertional mutagenesis screens and human oncogenes and tumour suppressor genes, validating the use of these screening strategies [41,47,49,51]. Furthermore, insertional mutagenesis has facilitated the identification of novel cancer genes, such as the oncogene Pim1 [52] and the pancreatic tumour suppressor gene Usp9x [53] -cancer genes identified in the mouse before being found to be relevant for human tumourigenesis. By performing these screens on a cancer pre-disposed background, insertional mutagenesis screens may reveal information about the underlying mechanisms of synergy between oncogenic and tumour suppressor pathways.…”