The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma

摘要

对在一个小鼠胰腺癌模型中与致癌基因、rnKrase~(G12D)合作的基因所做的一次“插入式突变rn发生”筛选，发现在所分析的近_200个不同肿rn瘤中的超过一半当中，Usp9x被破坏。这一发rn现是令人吃惊的，因为以前的工作表明，“去rn泛素化酶”LJSP9X促进肿瘤细胞存活。功能研rn究表明，Usp9x的失去通过在多个致癌信号通道上的一个效应来保护胰腺癌细胞不发生凋rn亡。在人类胰腺癌中，Usp9x表达经常失去，rn而且这种失去与该疾病更晚期的病情相关。因rn此，能够触发LJsp9x重新表达的方法对于胰腺rn癌的治疗可能会有用。%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 preneoplasia8 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 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-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.