Objective:Oncogenes have been shown to be drivers of non-small cell lung cancer (NSCLC),yet the tumor suppressing genes involved in lung carcinogenesis remain to be systematically investigated.This study aimed to identify tumor suppressing ubiquitin pathway genes (UPGs) that were critical to lung tumorigenesis.Methods:The 696 UPGs were silenced by an siRNA screening in NSCLC cells;the potential tumor suppressing UPGs were analyzed,and their clinical significance was investigated.Results:We reported that silencing of 11 UPGs resulted in enhanced proliferation of NSCLC cells,and four UPGs (UBL3,TRIM22,UBE2G2,and MARCH1) were significantly downregulated in tumor samples compared to that in normal lung tissues and their expression levels were positively associated with overall survival (OS) of NSCLC patients.Among these genes,UBL3 was the most significant one.UBL3 expression was decreased in tumor samples compared to that in paired normal lung tissues in 59/86 (68.6％) NSCLCs,was correlated with TNM stage and sex of NSCLC patients,and was significantly higher in non-smoking patients than in smoking patients.Silencing UBL3 accelerated cell proliferation and ectopic expression of UBL3 suppressed NSCLC in vitro and in vivo.Conclusions:These results showed that UBL3 represented a tumor suppressor in NSCLC and may have potential for use in therapeutics and for the prediction of clinical outcome of patients.