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Vaccinia-related kinase 2 drives pancreatic cancer progression by protecting Plk1 from Chfr-mediated degradation

Oncogene volume 40, pages 4663–4674 (2021)Cite this article

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Abstract

As a key cell cycle regulator, polo-like kinase 1 (Plk1) has been recognized as a crucial factor involved in the progression of pancreatic cancer (PC). However, its regulatory mechanism is poorly understood. Here, we present evidence that Plk1 is a novel substrate of vaccinia-related kinase 2 (VRK2), a serine-threonine kinase that is highly expressed and predicts poor prognosis in PC. VRK2 phosphorylates Plk1 at threonine 210 and protects it from ubiquitin-dependent proteasomal degradation. We showed that mechanistically complement factor H-related protein (CFHR), as a major E3 ligase, promotes Plk1 degradation by ubiquitinating it at lysine 209. Phosphorylation of Plk1 at threonine 210 by VRK2 interferes with the interaction of Chfr with Plk1 and antagonizes Plk1 ubiquitination, thereby stabilizing the Plk1 protein. Taken together, our data reveal a mechanism of Plk1 overexpression in PC and provide evidence for targeting VRK2 as a potential therapeutic strategy.

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Fig. 1: High VRK2 expression correlates with the poor prognosis of PC.
Fig. 2: VRK2 accelerates PC cells proliferation in vitro and in vivo.
Fig. 3: VRK2 regulates Plk1 protein expression and promotes PC cells proliferation.
Fig. 4: VRK2 stabilizes the expression of Plk1 protein by inhibiting proteasome-mediated Plk1 degradation.
Fig. 5: VRK2-mediated Plk1 Thr210 phosphorylation is necessary for the stabilization of Plk1.
Fig. 6: VRK2-mediated Plk1 phosphorylation disrupts Plk1 interaction with Chfr and protects Plk1 from degradation.
Fig. 7: Clinical PC tissues validated positive regulation of VRK2 on Plk1.

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Acknowledgements

This study was supported by the Scientific research and cultivation project of talents in the First Affiliated Hospital of Nanchang University (YFYPY202015).

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Author notes

  1. These authors contributed equally: Hengqing Zhu, Qing Li, Yulan Zhao.

Authors and Affiliations

  1. Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China

    Hengqing Zhu

  2. Department of Thyroid Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China

    Hengqing Zhu

  3. Department of Pathology, Second Affiliated Hospital of Nanchang University, Nanchang, China

    Qing Li

  4. Department of Ultrasound in Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China

    Yulan Zhao

  5. Department of Colorectal Surgery, 908th Hospital of Chinese People’s Liberation Army Joint, Nanchang, China

    Hong Peng

  6. Department of Ultrasound, Second Affiliated Hospital of Nanchang University, Nanchang, China

    Liangyun Guo

  7. Department of Pharmacy, Second Affiliated Hospital of Nanchang University, Nanchang, China

    Jing Zhu & Zi Jiang

  8. Department of Radiology, Second Affiliated Hospital of Nanchang University, Nanchang, China

    Zhaoxia Zeng

  9. Department of Burns, First Affiliated Hospital of Nanchang University, Nanchang, China

    Bin Xu

  10. Department of Neurology, Second Affiliated Hospital of Nanchang University, Nanchang, China

    Sisi Chen

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Contributions

SSC and BX conceived, designed and supervised the execution of the entire project. HQZ, QL and YLZ initiated the project, designed experiments, and carried out major western blot, bioinformatics, cellular and animal studies. HP and JZ helped to establish IHC staining and pathological analyses. LYG and ZJ were responsible for mass spectrometry analysis. ZXZ analyzed and interpreted the data. All authors have read and approved the final manuscript.

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Correspondence to Bin Xu or Sisi Chen.

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Zhu, H., Li, Q., Zhao, Y. et al. Vaccinia-related kinase 2 drives pancreatic cancer progression by protecting Plk1 from Chfr-mediated degradation. Oncogene 40, 4663–4674 (2021). https://doi.org/10.1038/s41388-021-01893-4

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