Abstract
Chemoresistance is an important cause of treatment failure in bladder cancer, and identifying genes that confer drug resistance is an important step toward developing new therapeutic strategies to improve treatment outcomes. In the present study, we show that gemcitabine plus cisplatin (GEM/DDP) therapy induces NF-κB signaling, which promotes p65-mediated transcriptional activation of OIP5. OIP5 recruits the E3 ubiquitin ligase TRIP12 to bind to and degrade the phosphatase PPP1CB, thereby enhancing the transcription factor activity of YBX1. This in turn upregulates drug-resistance-related genes under the transcriptional control of YBX1, leading to chemoresistance. Moreover, PPP1CB degradation can enhance the phosphorylation activity of IKKβ, triggering the NF-κB signaling cascade, which further stimulates OIP5 gene expression, thus forming a negative feedback regulatory loop. Consistently, elevated OIP5 expression was associated with chemoresistance and poor prognosis in patients with bladder cancer. Furthermore, we used a CRISPR/Cas9-based engineered gene circuit, which can monitor the progression of chemoresistance in real-time, to induce OIP5 knockout upon detection of increased NF-κB signaling. The gene circuit significantly inhibited tumor cell growth in vivo, underscoring the potential for synergy between gene therapy and chemotherapy in the treatment of cancer.
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Data availability
The gene expression data generated in this study are available in the SRA database (SRA: PRJNA1110839).
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Acknowledgements
This work was supported by National Key R&D Program of China (2019YFA0906000), Shenzhen Portion of Shenzhen-Hong Kong Science and Technology Innovation Cooperation Zone (HTHZQSWS- KCCYB-2023060). National Natural Science Foundation of China (82203459), Guangdong Special Support Program (2021JC06Y578), Fundamental Research Funds for the Central Universities, Sun Yat-sen University (59000-31610020), Shenzhen Municipal Government of China (CJGJZD20200617102403009), Sanming Project of the Shenzhen Health and Family Planning Commission (SZSM202011017), Shenzhen High-Level Hospital Construction Fund and the Shenzhen Institute of Synthetic Biology Scientific Research Program (ZTXM20214005), Shenzhen Key Medical Discipline Construction Fund (No. SZXK020), China Postdoctoral Science Foundation (2023T160436), Shenzhen High-Level Hospital Construction Fund, The research fund from Synthetic Biology Research Center of Shenzhen University.
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XTW, and TG contributed equally to this study. WRH, XTW, and TG conducted experiments and wrote the manuscript. LMN, and BBZ prepared and processed the clinical samples. HBX, and WH performed the data analyses. WRH, and XTW conceived of the study. WRH, supervised the study and revised the manuscript. All authors have read and approved the final manuscript.
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Wang, X., Guo, T., Niu, L. et al. Engineered targeting OIP5 sensitizes bladder cancer to chemotherapy resistance via TRIP12-PPP1CB-YBX1 axis. Oncogene (2024). https://doi.org/10.1038/s41388-024-03136-8
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DOI: https://doi.org/10.1038/s41388-024-03136-8