RBCK1 promotes chemotherapy resistance in bladder carcinoma by targeting HLTF.

Abstract

Bladder cancer remains highly prone to cisplatin resistance, which markedly limits therapeutic efficacy and contributes to poor clinical outcomes. Although dysregulation of E3 ubiquitin ligases has been implicated in tumor progression and drug resistance, the specific ligases that drive cisplatin resistance in bladder cancer and their underlying mechanisms remain incompletely defined. In this study, integrated analysis of public transcriptomic datasets identified RBCK1 as an aberrantly upregulated E3 ubiquitin ligase associated with malignant progression and cisplatin resistance in bladder cancer. Functional assays showed that RBCK1 promoted clonogenic survival and reduced cisplatin sensitivity in bladder cancer cells. Mechanistically, RBCK1 directly interacted with the helicase-like transcription factor HLTF and facilitated its ubiquitin-proteasome-dependent degradation, thereby decreasing HLTF protein stability. Loss of HLTF relieved suppression of the JAK2/STAT3 pathway and enhanced STAT3 activation. Rescue experiments further demonstrated that HLTF depletion attenuated the cisplatin-sensitizing effect induced by RBCK1 knockdown, whereas pharmacological inhibition of STAT3 with Stattic abrogated this resistance-restoring phenotype. Collectively, these findings identify an RBCK1-HLTF-JAK2/STAT3 regulatory axis that promotes cisplatin resistance in bladder cancer cells, and xenograft validation further supports the role of RBCK1 depletion in enhancing cisplatin response in vivo. Further clinical studies are warranted to determine the translational relevance of targeting this pathway in cisplatin-treated bladder cancer.