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Engineered targeting OIP5 sensitizes bladder cancer to chemotherapy resistance via TRIP12-PPP1CB-YBX1 axis

Oncogene (2024)Cite this article

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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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Fig. 1: OIP5 expression is induced by GEM/DDP and correlates with bladder cancer chemoresistance.
Fig. 2: OIP5 promotes resistance to GEM/DDP in vivo and in bladder cancer organoids.
Fig. 3: Binding of PPP1CB by OIP5 promotes proteasome-mediated degradation of PPP1CB.
Fig. 4: OIP5-TRIP12 mediates the ubiquitination-dependent degradation of PPP1CB.
Fig. 5: OIP5, TRIP12, and PPP1CB form a protein complex.
Fig. 6: PPP1CB-mediated YBX1 phosphorylation is controlled by the OIP5-TRIP12 axis.
Fig. 7: PPP1CB/NF-κB axis regulates OIP5 transcription in chemoresistant bladder cancer cells.

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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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  1. These authors contributed equally: Xianteng Wang, Ting Guo.

Authors and Affiliations

  1. Department of Urology, Shenzhen Institute of Translational Medicine, Medical Innovation Technology Transformation Center, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, International Cancer Center of Shenzhen University, Shenzhen, China

    Xianteng Wang, Liman Niu, Binbin Zheng, Haibo Xu & Weiren Huang

  2. Molecular Cancer Research Center, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen University, Shenzhen, China

    Xianteng Wang

  3. Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China

    Ting Guo & Weiren Huang

  4. Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China

    Ting Guo & Weiren Huang

  5. Graduate School, Guangxi University of Chinese Medicine, Nanning, China

    Ting Guo

  6. Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong, China

    Wei Huang

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Contributions

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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Correspondence to Weiren Huang.

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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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