Ubiquitination and deubiquitination are important posttranslational modifications involved in various cellular processes. To investigate the role of deubiquitinase (DUBs) in lung cancer progression, we analyzed correlation of DUB expression with survival data in a database linking TCGA survival data to gene expression. We found that low expression of ubiquitin specific protease 4 (USP4) was associated with low survival rate of lung cancer patients. Moreover, USP4 was downregulated in stemness enriched cancers. Thus, the effect of USP4 downregulation on tumor propagation in lung cancers were evaluated. Knockdown of USP4 in lung cancers enhanced NF-&kappaB activation and inflammatory responses. In addition, the capability of sphere formation and expression of stemness associated genes were elevated in USP4 knockdown cells. Further, knockdown of USP4 enhanced proliferation and expression molecule for resistant to immune therapy in lung cancers as well as enhanced resistance to chemotherapy drugs. Animal studies showed that reduction of USP4 expression in lung cancers enhanced tumor growth and increased inflammatory and stemness properties in tumors.
