Targeting KIF23 inhibits cell proliferation and primary chemoresistance in cervical cancer by inactivating the MYH9/MCM2/PCNA pathway.

backgroundKinesin family member 23 (KIF23) is recognised as an important tumour promoter involved in the pathogenesis of various cancers. However, its role and underlying molecular mechanisms in regulating cervical cancer (CC) growth and primary chemoresistance remain to be fully elucidated.

methodsThe expression and prognostic significance of KIF23 were initially assessed through bioinformatic analyses and subsequently validated in clinical specimens. To evaluate the effects of KIF23 on cell proliferation and cisplatin (DDP) sensitivity in CC cells, in vitro and in vivo experiments were conducted using CRISPR/Cas9 knockout, overexpression and mouse xenograft models. Co-immunoprecipitation, protein half-life assays and ubiquitination assays were employed to elucidate the interactions and regulatory mechanisms involving KIF23, myosin heavy chain 9 (MYH9), minichromosome maintenance protein 2 (MCM2) and proliferating cell nuclear antigen (PCNA), thereby revealing the molecular basis of KIF23-mediated CC progression and primary chemoresistance.

resultsKIF23 is highly expressed in CC tissues and is significantly correlated with poor prognosis and DDP resistance in patients. The knockout of KIF23 inhibited cell proliferation, induced G1-phase arrest and enhanced chemosensitivity to DDP. Mechanistically, the C-terminal domain of KIF23 was found to directly bind to the myosin tail domain of MYH9. This interaction stabilises MYH9 by recruiting deubiquitinase 7 (ubiquitin-specific protease 7 [USP7]), which removes K48-linked ubiquitin chains. The consequent upregulation of MYH9 promoted the recruitment of ubiquitin-specific protease 15 (USP15) to deubiquitinate MCM2, thereby preventing its degradation. Lysine 469 (K469) of MCM2 was identified as the key site for MYH9-induced deubiquitination. Furthermore, elevated MCM2 levels enhanced its binding to PCNA, thereby promoting CC cell proliferation.

conclusionsThese findings demonstrated that elevated KIF23 levels act as an unfavorable prognostic factor for CC by promoting cell proliferation and primary chemoresistance via the activation of the MYH9/MCM2/PCNA axis. Thus, KIF23 may represent a promising therapeutic target for improving clinical outcomes in CC. HIGHLIGHTS: Cisplatin treatment induces KIF23 expression in a concentration- and time-dependent manner. KIF23 recruits USP7, which removes the K48-linked ubiquitin chain of MYH9, thereby stabilising MYH9 and facilitating its nuclear transport. MYH9 recruits USP15, thereby stabilising MCM2, which, in turn, regulates the G1/S phase transition by binding to PCNA. Targeting the KIF23/MYH9/MCM2/PCNA axis sensitises cervical cancer cells to cisplatin.