JOSD2 promotes non-small cell lung cancer proliferation by removing K6-linked polyubiquitination from LKB1

Deubiquitinating enzymes (DUBs), frequently overactivated in cancers, are associated with tumorigenesis and regarded as promising therapeutic targets. However, the tumor-promoting role and underlying mechanism of DUBs in non-small cell lung cancer (NSCLC) are poorly understood. Through a global analysis of the contribution of 88 DUBs in NSCLC survival possibilities, we found that high expression of Josephin Domain-containing protein 2 (JOSD2) predicted the poor prognosis of patients. Depletion of JOSD2 significantly impeded NSCLC tumor growth in vivo in both NCI-H1299-derived xenografts and patient-derived xenografts. Mechanistically, JOSD2 functioned as a DUB by removing K6-linked polyubiquitination from LKB1, which was critical for maintaining LKB1-STRAD-MO25 complex integrity and hence its kinase activity. Furthermore, for the first time, we identified small molecule inhibitor of JOSD2 and the pharmacological inhibition of JOSD2 significantly arrested NSCLC proliferation both in vitro and in vivo. Notably, our findings demonstrate a crucial role of JOSD2 in hindering LKB1 activity, highlighting JOSD2 as a potential therapeutic target in NSCLC and providing its inhibitors as a promising strategy for NSCLC treatment. Overall design: mRNA profiles of knocking down JOSD2 in H1299 cells