The deubiquitinase OTUD1 inhibits non-small cell lung cancer progression by deubiquitinating and stabilizing KLF4.

Background: Lung cancer results in the highest mortality associated with cancer worldwide. Non-small cell cancer (NSCLC) is the leading subtype of lung cancer. Ovarian tumor protease (OTU) domain-containing protein 1 (OTUD1) is a member of the OTU subfamily of DUBs, and its function in NSCLC remains unclear.

Methods: GEPIA database was employed to reveal the expression level of OTUD1 in addition to Krüppel- like factor 4 (KLF4) in NSCLC tissue samples and prove the correlation between OTUD1 and KLF4. The protein level was estimated using western blot. Cell counting kit-8 (CCK-8) assay was used to detect cell viability and transwell assay was utilized to observe cell migration and invasion. Cycloheximide (CHX) was introduced to measure half-lives of KLF4 and deubiquitination assay was used to detect deubiquitination ability of OTUD1.

Results: OTUD1 expression was downregulated in NSCLC tissues and cells. Overexpression of OTUD1 inhibited NSCLC cell progression and it was promoted by knockdown of OTUD1. OTUD1 was positively correlated with KLF4 and stabilized KLF4 at protein level by deubiquitinating KLF4. Overexpressing KLF4 dramatically eliminated the effects of OTUD1 on the development of NSCLC cells.

Conclusions: Our study revealed that OTUD1 suppresses NSCLC progression by mediating KLF4 stabilization, which suggests a potential gene target for the future treatment of NSCLC.