KIF18A is a novel target of JNK1/c-Jun signaling pathway involved in tumorigenesis

Abstract

Background The mitogen-activated protein kinases (MAPKs) play a crucial role in various cellular processes, including gene expression. Among these, MAPK, MAPK8 (JNK1) specifically activates the oncogene—c-Jun. KIF18A, a kinesin protein, functions both as a promoter and an inhibitor of microtubule dynamics. Aberrant expression of KIF18A is linked with tumorigenesis, but its involvement in the JNK1/c-Jun pathway remains unclear. This study investigates the regulatory relationship between KIF18A and the JNK1-c-Jun pathway in cervical cancer. Methods We utilized the Genomic Data Commons (GDC) data portal to screen for KIF18A-related protein kinases in cervical cancer. All mRNA expression data of all cancer types obtained from TCGA database was investigated to further confirm the correlation between JNK1 and KIF18A. Expression levels of pc-Jun, c-Jun and KIF18A were examined through western blotting (WB) after inhibition of JNK1 in HeLa cells. In silico analysis was performed to identify the TF binding motifs on KIF18A promoter. Chromatin immunoprecipitation (ChIP) assay and Luciferase assay were used to confirm the c-Jun's direct binding and activation of the KIF18A promoter. Effect of c-Jun/KIF18A on cell growth was assessed by MTT assay and colony assay. Results A total of 193 kinases exhibited a close correlation with KIF18A, with JNK1 displaying a notably high correlation in cervical cancer and other tumor types. Inhibition of JNK1 in HeLa cells resulted in reduced KIF18A expression and decreased phosphorylation of c-Jun. Through In-silico analysis, c-Jun was identified as a transcription factor (TF) capable of binding to the KIF18A promoter. Confirmatory ChIP and Luciferase assays established c-Jun's direct binding and activation of the KIF18A promoter. Knockdown of c-Jun inhibited cancer cell proliferation by suppressing KIF18A transcription. Conclusions In summary, the JNK1/c-Jun pathway activates KIF18A expression, a process essential for cervical cancer cell proliferation. Targeting the JNK/c-Jun/KIF18A axis holds promise as a novel therapeutic approach in cancer treatment.