The NEK8/ALYREF axis promotes cisplatin resistance in bladder cancer by stabilizing CDK18 mRNA to facilitate DNA damage repair.

Abstract

Cisplatin-based chemotherapy remains a standard treatment for advanced bladder cancer (BCa), however, the development of chemoresistance substantially compromises its clinical efficacy and patient prognosis. In this study, we investigated the functional role of NEK8 in cisplatin resistance in BCa and elucidated its underlying molecular mechanisms. We found that NEK8 was significantly upregulated in cisplatin-resistant BCa and was associated with unfavorable prognosis. Functional studies demonstrated that NEK8 promoted cisplatin resistance and tumor progression both in vitro and in vivo. Mechanistically, NEK8 directly interacted with ALYREF and promoted its phosphorylation and subsequent nuclear translocation. Nuclear ALYREF recognized m5C-modified CDK18 mRNA and enhanced its stability, resulting in increased CDK18 expression. Elevated CDK18 facilitated DNA damage repair, ultimately driving cisplatin resistance in BCa. Collectively, we identified a NEK8-mediated mechanism in which ALYREF phosphorylation and nuclear translocation enhance CDK18 mRNA stability and DNA damage repair, thereby driving cisplatin resistance in BCa.