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PARP10 suppresses tumor metastasis through regulation of Aurora A activity

Oncogene volume 37, pages 2921–2935 (2018)Cite this article

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Abstract

ADP-ribosylation, including poly-ADP-ribosylation (PARylation) and mono-ADP-ribosylation (MARylation), is a multifunctional post-translational modification catalyzed by intracellular ADP-ribosyltransferases (ARTDs or PARPs). Although PARylation has been investigated most thoroughly, the function of MARylation is currently largely undefined. Here, we provide evidences that deficiency of PARP10, a mono-ADP-ribosyltransferase, markedly increased the migration and invasion of tumor cells through regulation of epithelial–mesenchymal transition (EMT), and PARP10 inhibited tumor metastasis in vivo, which was dependent on its enzyme activity. Mechanistically, we found that PARP10 interacted with and mono-ADP-ribosylated Aurora A, and inhibited its kinase activity, thereby regulating its downstream signaling. Moreover, the expression level of PARP10 was downregulated in intrahepatic metastatic hepatocellular carcinoma (HCC) compared with its corresponding primary HCC and adjacent non-tumorous tissues. Taken together, our results indicated that PARP10 has an important role in tumor metastasis suppression via negatively regulation of Aurora A activity.

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References

  1. Gibson BA, Kraus WL. New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat Rev Mol Cell Biol. 2012;13:411–24.

    Article  CAS  PubMed  Google Scholar 

  2. Schreiber V, Dantzer F, Ame JC, Murcia GD. Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol. 2006;7:517–28.

    Article  CAS  PubMed  Google Scholar 

  3. Kaufmann M, Feijs KLH, Lüscher B. Function and regulation of the mono-ADP-ribosyltransferase ARTD10. Curr Top Microbiol Imumunol. 2015;384:167–88.

    CAS  Google Scholar 

  4. Kleine H, Poreba E, Lesniewicz K, Hassa PO, Hottiger MO, Litchfield DW, et al. Substrate-assisted catalysis by PARP10 limits its activity to mono-ADP-ribosylation. Mol Cell. 2008;32:57–59.

    Article  CAS  PubMed  Google Scholar 

  5. Hottiger MO, Hassa PO, Lüscher B, Schüler H, Kochnolte F. Toward a unified nomenclature for mammalian ADP-ribosyltransferases. Trends Biochem Sci. 2010;35:208–19.

    Article  CAS  PubMed  Google Scholar 

  6. Hassa PO, Haenni SS, Elser M, Hottiger MO. Nuclear ADP-ribosylation reactions in mammalian cells: where are we today and where are we going? Microbiol Mol Biol Rev. 2006;70:789–829.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Vyas S, Chang P. New PARP targets for cancer therapy. Nat Rev Cancer. 2014;14:502–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yu M, Schreek S, Cerni C, Schamberger C, Lesniewicz K, Poreba E, et al. PARP-10, a novel Myc-interacting protein with poly(ADP-ribose) polymerase activity, inhibits transformation. Oncogene. 2005;24:1982–93.

    Article  CAS  PubMed  Google Scholar 

  9. Kleine H, Herrmann A, Lamark T, Forst AH, Verheugd P, Lüscherfirzlaff J, et al. Dynamic subcellular localization of the mono-ADP-ribosyltransferase ARTD10 and interaction with the ubiquitin receptor p62. Cell Commun Signal. 2012;10:28–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Herzog N, Hartkamp JD, Verheugd P, Treude F, Forst AH, Feijs KL, et al. Caspase-dependent cleavage of the mono-ADP-ribosyltransferase ARTD10 interferes with its pro-apoptotic function. Febs J. 2013;280:1330–43.

    Article  CAS  PubMed  Google Scholar 

  11. Feijs KL, Kleine H, Braczynski A, Forst AH, Herzog N, Verheugd P, et al. ARTD10 substrate identification on protein microarrays: regulation of GSK3β by mono-ADP-ribosylation. Cell Commun Signal. 2013;11:5–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Verheugd P, Forst AH, Milke L, Herzog N, Feijs KLH, Kremmer E, et al. Regulation of NF-κB signalling by the mono-ADP-ribosyltransferase ARTD10. Nature. Communications. 2013;4:1683–93.

    Google Scholar 

  13. Le C, Ran FA, Cox D, Lin S, Barretto R, Habib N, et al. Multiplex genome engineering using CRISPR/Cas systems. Science. 2013;339:819–23.

    Article  CAS  Google Scholar 

  14. Gavert N, Benze’Ev A. Epithelial–mesenchymal transition and the invasive potential of tumors. Trends Mol Med. 2008;14:199–209.

    Article  CAS  PubMed  Google Scholar 

  15. Hu X, Zhao Y, Wei L, Zhu B, Song D, Wang J, et al. CCDC178 promotes hepatocellular carcinoma metastasis through modulation of anoikis. Oncogene. 2017;36:4047–59.

    Article  CAS  PubMed  Google Scholar 

  16. Yan M, Wang C, He B, Yang M, Tong M, Long Z, et al. Aurora A kinase: a potent oncogene and target for cancer therapy. Med Res Rev. 2016;36:1036–79.

    Article  PubMed  Google Scholar 

  17. Feijs KLH, Forst AH, Verheugd P, Lüscher B. Macrodomain-containing proteins: regulating new intracellular functions of mono(ADP-ribosyl)ation. Nat Rev Mol Cell Biol. 2013;14:443–57.

    Article  PubMed  CAS  Google Scholar 

  18. Forst Alexandra H, Karlberg T, Herzog N, Thorsell AG, Gross A, Feijs Karla LH, et al. Recognition of mono-ADP-ribosylated ARTD10 substrates by ARTD8 macrodomains. Structure. 2013;21:462–75.

    Article  CAS  PubMed  Google Scholar 

  19. Wang LH, Xiang J, Yan M, Zhang Y, Zhao Y, Yue CF, et al. The mitotic kinase Aurora A induces mammary cell migration and breast cancer metastasis by activating the Cofilin-F-actin pathway. Cancer Res. 2010;70:9118–28.

    Article  CAS  PubMed  Google Scholar 

  20. D’Assoro AB, Liu T, Quatraro C, Amato A, Opyrchal M, Leontovich A, et al. The mitotic kinase Aurora A promotes distant metastases by inducing epithelial-to-mesenchymal transition in ERα+ breast cancer cells. Oncogene. 2014;33:599–610.

    Article  CAS  PubMed  Google Scholar 

  21. Nicolae CM, Aho ER, Vlahos AH, Choe KN, De S, Karras GI, et al. The ADP-ribosyltransferase PARP10/ARTD10 interacts with proliferating cell nuclear antigen (PCNA) and is required for DNA damage tolerance. J Biol Chem. 2014;289:13627–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhao ZS, Lim JPNg YW, Lim L, Manser E. The GIT-associated kinase PAK targets to the centrosome and regulates Aurora A. Mol Cell. 2005;20:237–49.

    Article  CAS  PubMed  Google Scholar 

  23. Marumoto T, Zhang D, Saya H. Aurora A: a guardian of poles. Nat Rev Cancer. 2005;5:42–50.

    Article  CAS  PubMed  Google Scholar 

  24. Tatsuka M, Sato S, Kanda A, Miki T, Kamata N, Kitajima S, et al. Oncogenic role of nuclear accumulated Aurora A. Mol Carcinog. 2009;48:810–20.

    Article  CAS  PubMed  Google Scholar 

  25. Yang N, Wang C, Wang Z, Zona S, Lin SX, Wang X, et al. FOXM1 recruits nuclear Aurora kinase A to participate in a positive feedback loop essential for the self-renewal of breast cancer stem cells. Oncogene. 2017;36:3428–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zheng F, Yue C, Li G, He B, Wei C, Xi W, et al. Nuclear AURKA acquires kinase-independent transactivating function to enhance breast cancer stem cell phenotype. Nature Commun. 2016;7:1–17.

    Google Scholar 

  27. Guan Z, Wang XR, Zhu XF, Huang XF, Xu J, Wang LH, et al. Aurora A, a negative prognostic marker, increases migration and decreases radiosensitivity in cancer cells. Cancer Res. 2007;67:10436–44.

    Article  CAS  PubMed  Google Scholar 

  28. Wang X, Lu N, Niu B, Chen X, Xie J, Cheng N. Overexpression of Aurora A enhances invasion and matrix metalloproteinase-2 expression in esophageal squamous cell carcinoma cells. Mol Cancer Res. 2012;10:588–96.

    Article  CAS  PubMed  Google Scholar 

  29. Karin M. Nuclear factor-kappaB in cancer development and progression. Nature. 2006;441:431–6.

    Article  CAS  PubMed  Google Scholar 

  30. Chen T, Li J, Xu M, Zhao Q, Hou Y, Yao L, et al. PKCε phosphorylates MIIP and promotes colorectal cancer metastasis through inhibition of RelA deacetylation. Nature Commun. 2017;8:1–11.

    Article  CAS  Google Scholar 

  31. Maier HJ, Schmidt-Strassburger U, Huber MA, Wiedemann EM, Beug H, Wirth T. NF-kappaB promotes epithelial–mesenchymal transition, migration and invasion of pancreatic carcinoma cells. Cancer Lett. 2010;295:214–28.

    Article  CAS  PubMed  Google Scholar 

  32. Wang J, Zhu C, Song D, Xia R, Yu W, Dang Y, et al. Epigallocatechin-3-gallate enhances ER stress-induced cancer cell apoptosis by directly targeting PARP16 activity. Cell Death Discov. 2017;3:17034–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wu D, Liu G, Liu Y, Saiyin H, Wang C, Wei Z, et al. Zinc finger protein 191 inhibits hepatocellular carcinoma metastasis through discs large 1‐mediated yes‐associated protein inactivation. Hepatology. 2016;64:1148–62.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Yongjun Dang at School of Basic Medical Science, Fudan University for fruitful scientific discussions and sharing some reagents.

Funding

This work was supported by national key research and development plan (2016YFC0902401to JW); the National Natural Science Foundation of China (81272250 and 81472619 to JW) and the National Key Sci-Tech Special Project of China (2013ZX10002010-08 to JW).

Author’s contributions

YZ designed the study, conducted most of the experiments, and wrote the manuscript. XH provided advices about the experiments. ZL performed the statistical analysis. LW, DS, JW, and LY contributed to the manuscript completion. JW conceived the study, provided overall guidance, and contributed to the manuscript completion.

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Authors and Affiliations

  1. The State Key Laboratory of Genetic Engineering, School of Life Science and Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China

    Yahui Zhao, Xiaoding Hu, Dan Song, Juanjuan Wang, Lifang You, Hexige Saiyin, Wenbo Yu, Long Yu & Jiaxue Wu

  2. Department of Oncology, The 401 Hospital of PLA, Qingdao, People’s Republic of China

    Li Wei

  3. Shanghai Applied Protein Technology Co., Ltd, Shanghai, People’s Republic of China

    Zhaojie Li

  4. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, People’s Republic of China

    Jin Ding

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  1. Yahui Zhao
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Correspondence to Jiaxue Wu.

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Zhao, Y., Hu, X., Wei, L. et al. PARP10 suppresses tumor metastasis through regulation of Aurora A activity. Oncogene 37, 2921–2935 (2018). https://doi.org/10.1038/s41388-018-0168-5

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