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PPIP5K2 promotes colorectal carcinoma pathogenesis through facilitating DNA homologous recombination repair

Oncogene volume 40, pages 6680–6691 (2021)Cite this article

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Abstract

Colorectal carcinoma (CRC) is the second most deadly cancer worldwide. Therapies that take advantage of DNA repair defects have been explored in various tumors but not yet systematically in CRC. Here, we found that Diphosphoinositol Pentakisphosphate Kinase 2 (PPIP5K2), an inositol pyrophosphate kinase, was highly expressed in CRC and associated with a poor prognosis of CRC patients. In vitro and in vivo functional studies demonstrated that PPIP5K2 could promote the proliferation and migration ability of CRC cells independent of its inositol pyrophosphate kinase activity. Mechanically, S1006 dephosphorylation of PPIP5K2 could accelerate its dissociation with 14-3-3 in the cytoplasm, resulting in more nuclear distribution. Moreover, DNA damage treatments such as doxorubicin (DOX) or irradiation (IR) could induce nuclear translocation of PPIP5K2, which subsequently promoted homologous recombination (HR) repair by binding and recruiting RPA70 to the DNA damage site as a novel scaffold protein. Importantly, we verified that S1006 dephosphorylation of PPIP5K2 could significantly enhance the DNA repair ability of CRC cells through a series of DNA repair phenotype assays. In conclusion, PPIP5K2 is critical for enhancing the survival of CRC cells via facilitating DNA HR repair. Our findings revealed an unrecognized biological function and mechanism model of PPIP5K2 dependent on S1006 phosphorylation and provided a potential therapeutic target for CRC patients.

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Fig. 1: PPIP5K2 promotes CRC tumorigenesis and is associated with a poor prognosis.
Fig. 2: 14-3-3γ/τ mediates the nuclear translocation of PPIP5K2 via dephosphorylating at the S1006 site.
Fig. 3: PPIP5K2 interacts with RPA70 and accumulates at DNA damage sites.
Fig. 4: PPIP5K2 participates in DNA damage response independent of its kinase activity.
Fig. 5: Dephosphorylation of PPIP5K2-S1006 accelerates DNA damage response.
Fig. 6: PPIP5K2 depletion impairs the loading of RPA70 and RAD51 to DSBs.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request. The authenticity of this article has been validated by uploading the key raw data onto the Research Data Deposit public platform (www.researchdata.org.cn), with the approval RDD number as RDDB2021481511.

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Acknowledgements

This work was supported by grants from the National Key R&D Program of China [grant number 2017YFC1309000]; the National Natural Science Foundation of China [grant numbers 81972227, 81730072, 82072608, 81872001, and 82002467]; the Natural Science Foundation of Guangdong [grant numbers 2020A151501021 and 2020A1515011020]; the Guangzhou Science and Technology Plan Projects [grant number 201904020044] and the China Postdoctoral Science Foundation (2020M672999).

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  1. These authors contributed equally: Chen-Hui Cao, Han Ling, Kai Han, Xiao-Peng Lu.

Authors and Affiliations

  1. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China

    Chen-Hui Cao, Han Ling, Kai Han, Mu-Yan Cai, Jing-Hua Cao, Jie Zhou, Zhi-Cheng Xiang, Jie-Wei Chen, Si Li, Jin-Long Lin, Jin-Ling Duan, Jie Luo, Yu-Jing Fang, Zhi-Zhong Pan, Feng Wang, Dan Xie & Feng-Wei Wang

  2. Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China

    Kai Han, Yu-Jing Fang & Zhi-Zhong Pan

  3. Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen, 518055, China

    Xiao-Peng Lu

  4. Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China

    Mu-Yan Cai, Jie-Wei Chen & Dan Xie

  5. Department of Pathology, Southern Medical University, Guangzhou, 510060, China

    Li Liang

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Contributions

D.X. and F.-W.W. conceived and devised the study. C.-H.C. and F.-W.W. designed the experiments and analysis. H.L., K.H., X.-P.L., J.-H.C., J.Z., Z.-C.X., S.L., J.-L.L., J.-L.D. and J. L., performed the experiments. M.-Y.C., L.L. and J.-W.C. performed bioinformatics and statistical analysis. C.-H.C., H.L. and K.H. analyzed and interpreted the data. Y.-J.F., Z.-Z.P. and F.W. provided CRC patients tissue samples and clinical information. D.X. and F.-W.W. supervised the research and together with C.-H.C., H.L. and K.H. wrote the paper. All authors approved the submitted paper.

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Correspondence to Dan Xie or Feng-Wei Wang.

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Cao, CH., Ling, H., Han, K. et al. PPIP5K2 promotes colorectal carcinoma pathogenesis through facilitating DNA homologous recombination repair. Oncogene 40, 6680–6691 (2021). https://doi.org/10.1038/s41388-021-02052-5

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