摘要The transcription factor STAT3 is a promising target for the treatment of non-small cell lung cancer(NSCLC).STAT3 activity is mainly dependent on phosphorylation at tyrosine 705(pSTAT3-Y705),but the modulation on pSTAT3-Y705 is elusive.By screening a library of deubiquitinases(Dubs),we found that the Otub1 increases STAT3 transcriptional activity.As a Dub,Otub1 binds to pSTAT3-Y705 and specifically abolishes its K48-linked ubiquitination,therefore preventing its degradation and promoting NSCLC cell survival.The Otub1/pSTAT3-Y705 axis could be a potential target for the treatment of NSCLC.To explore this concept,we screen libraries of FDA-approved drugs and natural products based on STAT3-recognition element-driven luciferase assay,from which crizotinib is found to block pSTAT3-Y705 deubiquitination and promotes its degradation.Different from its known action to induce ALK positive NSCLC cell apoptosis,crizotinib suppresses ALK-intact NSCLC cell proliferation and colony formation but not apoptosis.Furthermore,crizotinib also suppresses NSCLC xenograft growth in mice.Taken together,these findings identify Otub1 as the first deubiquitinase of pSTAT3-Y705 and provide that the Otub1/pSTAT3-Y705 axis is a promising target for the treatment of NSCLC.