KIF18A Is a Novel Target of JNK1/c-Jun Signaling Pathway Involved in Cervical Tumorigenesis

Abstract

Cervical cancer remains a significant global health concern. KIF18A, a kinesin motor protein regulating microtubule dynamics during mitosis, is frequently overexpressed in various cancers, but its regulatory mechanisms are poorly understood. This study investigates KIF18A's role in cervical cancer and its regulation by the JNK1/c-Jun signaling pathway. Cell growth was assessed in vitro using MTT and colony formation assays, and in vivo using a nude mouse xenograft model with KIF18A knockdown HeLa cells. The Genomic Data Commons (GDC) data portal was used to identify KIF18A-related protein kinases in cervical cancer. Western blot analysis was employed to analyze phosphor-c-Jun, c-Jun, and KIF18A expression levels following JNK1 inhibition, c-Jun knockdown/overexpression, and KIF18A knockdown in cervical cancer cells. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were performed to assess c-Jun binding and transcriptional activity of the KIF18A promoter. KIF18A knockdown significantly impaired cervical cancer cell growth both in vitro and in vivo. A strong positive correlation was observed between JNK1 and KIF18A expression in cervical and other cancers. JNK1 inhibition decreased both KIF18A expression and c-Jun phosphorylation. c-Jun was found to directly bind to and activate the KIF18A promoter. Furthermore, c-Jun knockdown inhibited cervical cancer cell growth, and this effect was partially rescued by KIF18A overexpression. This study demonstrates that the JNK1/c-Jun pathway activates KIF18A expression, which is essential for cervical cancer cell growth. Targeting the JNK/c-Jun/KIF18A axis may represent a promising novel therapeutic strategy for cancer treatment.