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Overexpression of Pin1 regulated by TOP2A, which subsequently stabilizes Pyk2 to promote bortezomib resistance in multiple myeloma

Cancer Gene Therapy volume 32, pages 22–37 (2025)Cite this article

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Abstract

Multiple myeloma (MM), a hematological malignancy of plasma cells, has remained largely incurable owing to drug resistance and disease relapse, which requires novel therapeutic targets and treatment approaches. Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) acts as an oncoprotein linked to the development of various tumors. However, the functional consequence of Pin1 overexpression in modulating MM biology has not been established. In the present study, we show that Pin1 expression is highly variable in myeloma cell lines and primary MMs and that high Pin1 expression is associated with poor survival of MM patients. Next, TOP2A is identified to be a Pin1 promoter-binding protein and CK2 activates TOP2A to promote the expression level of Pin1. Additionally, we demonstrate that Pin1 positively modulates the stability and function of Pyk2 to enhance bortezomib resistance in MM. Pin1 recognizes three phosphorylated Ser/Thr-Pro motifs in Pyk2 via its WW domain and increases the cellular levels of Pyk2 in an isomerase activity-dependent manner by inhibiting the ubiquitination and proteasomal degradation of Pyk2. Moreover, Pin1 inhibition combined with Pyk2 inhibition decreases myeloma burden both in vitro and in vivo. Altogether, our findings reveal the tumor-promoting role of Pin1 in MM and provide evidence that targeting Pin1 could be a therapeutic strategy for MM.

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Fig. 1: Pin1 is overexpressed in MM, and elevated Pin1 predicts an adverse prognosis in MM patients.
Fig. 2: Human myeloma cells display variable levels of Pin1 expression.
Fig. 3: TOP2A was identified as a Pin1 promoter-binding protein, and both TOP2A and Pin1 were prognostic factors of overall survival in MM patients.
Fig. 4: The expression and function of Pin1 were regulated by TOP2A in MM cells.
Fig. 5: CK2 induces TOP2A-mediated upregulation of Pin1.
Fig. 6: Pyk2 abundance is positively correlated with Pin1 expression in MM cells.
Fig. 7: Pin1 interacts with Pyk2 via its WW domain in a phosphorylation-dependent manner.
Fig. 8: Pin1 binds to Pyk2 and enhances the stability of Pyk2.
Fig. 9: Pin1 increases the stability of Pyk2 by suppressing its ubiquitination.
Fig. 10: Pin1 inhibition combined with Pyk2 inhibition decreases myeloma burden.

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Data availability

All data generated or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank all authors for their contributions.

Funding

This work was supported by Guangdong Basic and Applied Basic Research Foundation (2021A1515110974), the National Natural Science Foundation of China (82270233, U2001224), China postdoctoral science foundation (2023M741554), the Science and Technology Program of Guangzhou (202201011041).

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  1. These authors contributed equally: Honghao Zhang, Jianyu Chen, Yabo Meng.

Authors and Affiliations

  1. Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China

    Honghao Zhang, Jianyu Chen, Yabo Meng, Qingyan Cen, Hao Wang, Xiangyang Ding, Kexin Ai, Yulu Yang, Yang Gao, Yingqi Qiu, Yuxing Hu, Meifang Li, Yanjie He & Yuhua Li

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Contributions

YhL, YjH, MfL, and HhZ conceived the project. HhZ, JyC, YbM, HW, and QyC performed the experiments. HhZ, XyD, KxA, YlY, and YG analyzed the data. HhZ, YqQ, and YxH performed the informatics analysis. HhZ, YjH, MfL, and YhL wrote the manuscript.

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Correspondence to Meifang Li, Yanjie He or Yuhua Li.

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This study was conducted in accordance with the ARRIVE guidelines. The design and final reports of this study complied with the Helsinki Declaration and were approved by the Ethical Review Board of Zhujiang Hospital of Southern Medical University (Guangzhou, China). Informed consent was obtained from all subjects involved in the study. The in vivo experiments were carried out in accordance with the Southern Medical University’s Policy on Care and Use of Laboratory Animals and ARRIVE guidelines.

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Zhang, H., Chen, J., Meng, Y. et al. Overexpression of Pin1 regulated by TOP2A, which subsequently stabilizes Pyk2 to promote bortezomib resistance in multiple myeloma. Cancer Gene Ther 32, 22–37 (2025). https://doi.org/10.1038/s41417-024-00845-w

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