KIF14 silencing suppresses cell proliferation and enhances chemosensitivity by modulating 53BP1 nucleocytoplasmic shuttling in non-WNT/non-SHH medulloblastoma.

Abstract

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. The non-WNT/non-SHH subtypes (Groups 3 and 4) exhibit high genetic heterogeneity and limited therapeutic options. Kinesin family member 14 (KIF14) is selectively expressed during nervous system development. However, its role in non-WNT/non-SHH MB remains poorly understood. In this study, analysis of the GEO database revealed that high KIF14 expression correlates with poor prognosis in patients with non-WNT/non-SHH MB. Silencing KIF14 in MB cells impaired cytokinesis, leading to p53-mediated cell cycle arrest and apoptosis. Mechanistically, KIF14 knockdown disrupted the nucleocytoplasmic shuttling of the p53-binding protein 53BP1, resulting in its nuclear accumulation. This shift inhibited homologous recombination (HR)-mediated repair of DNA double-stranded breaks (DSBs), thereby enhancing cisplatin-induced DNA damage. In vitro experiments and intracranial orthotopic xenograft models confirmed that KIF14 silencing potentiates the antitumor efficacy of cisplatin treatment. Overall, these findings highlight the critical role of KIF14 in promoting cell proliferation and DNA repair in non-WNT/non-SHH MB and suggest that targeting KIF14 may represent a novel therapeutic strategy to enhance the efficacy of DNA-damaging agents in this challenging MB subtype.