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Zinc-finger antiviral protein acts as a tumor suppressor in colorectal cancer

Oncogene volume 39, pages 5995–6008 (2020)Cite this article

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Abstract

Avoiding immune destruction is essential for tumorigenesis. Current research into the interaction between tumor and immunological niches complement tumor pathology beyond cancer genetics. Intrinsic host defense immunity is a specialized innate immunity component to restrict viral infection. However, whether intrinsic immunity participates in tumor pathology is unclear. Previously, we identified a zinc-finger antiviral protein ZAP that is commonly downregulated in a panel of clinical cancer specimens. However, whether ZAP has an impact on tumor development was unknown. Here we report ZAP as a genuine tumor suppressor. Pan-caner analysis with TCGA data from 712 patients and large-scale immunohistochemistry in tissue microarrays from 1552 patients reveal that ZAP is prevalently downregulated, and associated with poor survival in liver, colon, and bladder cancer patients. Ectopic over-expression of ZAP inhibits the malignant phenotypes of colorectal tumor by cell cycle arrest. Using RNA immunoprecipitation and RNA decay assays, we demonstrate that ZAP directly and specifically binds to and degrades the transcript of TRAILR4, which in turn represses TRAILR4 expression and inhibits the aggressiveness of colorectal cancer cells. Furthermore, our CRISPR-engineered mice models show that loss-of-function of ZAP synergizes with APC-deficiency to drive malignant colorectal cancer in vivo. Overall, we identify a previously unknown function of the antiviral factor ZAP in colorectal tumorigenesis, linking intrinsic immunity to tumor pathogenetics.

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Fig. 1: ZAP is downregulated in pan cancer and associated with poor survival.
Fig. 2: ZAP suppresses malignant phenotypes of colorectal cancer in vitro and in vivo.
Fig. 3: ZAP selectively binds and degrades TRAILR4 mRNA.
Fig. 4: ZAP inhibits tumorigenesis by degrading TRAILR4 mRNA.
Fig. 5: Knockout of Zap promotes colorectal carcinogenesis in ApcMin/+ mice.

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References

  1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    CAS  PubMed  Google Scholar 

  2. Ribas A. Adaptive immune resistance: how cancer protects from immune attack. Cancer Discov. 2015;5:915–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Feng M, Jiang W, Kim BYS, Zhang CC, Fu YX, Weissman IL. Phagocytosis checkpoints as new targets for cancer immunotherapy. Nat Rev Cancer. 2019;19:568–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359:1350–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Thorsson V, Gibbs DL, Brown SD, Wolf D, Bortone DS, Ou Yang TH, et al. The immune landscape of cancer. Immunity. 2018;48:812–30. e814.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Munoz-Fontela C, Mandinova A, Aaronson SA, Lee SW. Emerging roles of p53 and other tumour-suppressor genes in immune regulation. Nat Rev Immunol. 2016;16:741–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Textor S, Fiegler N, Arnold A, Porgador A, Hofmann TG, Cerwenka A. Human NK cells are alerted to induction of p53 in cancer cells by upregulation of the NKG2D ligands ULBP1 and ULBP2. Cancer Res. 2011;71:5998–6009.

    CAS  PubMed  Google Scholar 

  8. Yoon KW, Byun S, Kwon E, Hwang SY, Chu K, Hiraki M, et al. Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53. Science. 2015;349:1261669.

    PubMed  PubMed Central  Google Scholar 

  9. Snell LM, McGaha TL, Brooks DG. Type I interferon in chronic virus infection and cancer. Trends Immunol. 2017;38:542–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Parker BS, Rautela J, Hertzog PJ. Antitumour actions of interferons: implications for cancer therapy. Nat Rev Cancer. 2016;16:131–44.

    PubMed  Google Scholar 

  11. Zitvogel L, Galluzzi L, Kepp O, Smyth MJ, Kroemer G. Type I interferons in anticancer immunity. Nat Rev Immunol. 2015;15:405–14.

    CAS  PubMed  Google Scholar 

  12. Dunn GP, Koebel CM, Schreiber RD. Interferons, immunity and cancer immunoediting. Nat Rev Immunol. 2006;6:836–48.

    CAS  PubMed  Google Scholar 

  13. Lin Y, Zhang H, Liang J, Li K, Zhu W, Fu L, et al. Identification and characterization of alphavirus M1 as a selective oncolytic virus targeting ZAP-defective human cancers. Proc Natl Acad Sci USA. 2014;111:E4504–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Bick MJ, Carroll JW, Gao G, Goff SP, Rice CM, MacDonald MR. Expression of the zinc-finger antiviral protein inhibits alphavirus replication. J Virol. 2003;77:11555–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Chiu HP, Chiu H, Yang CF, Lee YL, Chiu FL, Kuo HC, et al. Inhibition of Japanese encephalitis virus infection by the host zinc-finger antiviral protein. PLoS Pathog. 2018;14:e1007166.

    PubMed  PubMed Central  Google Scholar 

  16. Gao G, Guo X, Goff SP. Inhibition of retroviral RNA production by ZAP, a CCCH-type zinc finger protein. Science. 2002;297:1703–6.

    CAS  PubMed  Google Scholar 

  17. Guo X, Carroll JW, Macdonald MR, Goff SP, Gao G. The zinc finger antiviral protein directly binds to specific viral mRNAs through the CCCH zinc finger motifs. J Virol. 2004;78:12781–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Guo X, Ma J, Sun J, Gao G. The zinc-finger antiviral protein recruits the RNA processing exosome to degrade the target mRNA. Proc Natl Acad Sci USA. 2007;104:151–6.

    CAS  PubMed  Google Scholar 

  19. Lee H, Komano J, Saitoh Y, Yamaoka S, Kozaki T, Misawa T, et al. Zinc-finger antiviral protein mediates retinoic acid inducible gene I-like receptor-independent antiviral response to murine leukemia virus. Proc Natl Acad Sci USA. 2013;110:12379–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Liu CH, Zhou L, Chen G, Krug RM. Battle between influenza A virus and a newly identified antiviral activity of the PARP-containing ZAPL protein. Proc Natl Acad Sci USA. 2015;112:14048–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. MacDonald MR, Machlin ES, Albin OR, Levy DE. The zinc finger antiviral protein acts synergistically with an interferon-induced factor for maximal activity against alphaviruses. J Virol. 2007;81:13509–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Mao R, Nie H, Cai D, Zhang J, Liu H, Yan R, et al. Inhibition of hepatitis B virus replication by the host zinc finger antiviral protein. PLoS Pathog. 2013;9:e1003494.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Muller S, Moller P, Bick MJ, Wurr S, Becker S, Gunther S, et al. Inhibition of filovirus replication by the zinc finger antiviral protein. J Virol. 2007;81:2391–400.

    PubMed  Google Scholar 

  24. Xuan Y, Liu L, Shen S, Deng H, Gao G. Zinc finger antiviral protein inhibits murine gammaherpesvirus 68 M2 expression and regulates viral latency in cultured cells. J Virol. 2012;86:12431–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhu Y, Chen G, Lv F, Wang X, Ji X, Xu Y, et al. Zinc-finger antiviral protein inhibits HIV-1 infection by selectively targeting multiply spliced viral mRNAs for degradation. Proc Natl Acad Sci USA. 2011;108:15834–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhu Y, Wang X, Goff SP, Gao G. Translational repression precedes and is required for ZAP-mediated mRNA decay. EMBO J. 2012;31:4236–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Todorova T, Bock FJ, Chang P. PARP13 regulates cellular mRNA post-transcriptionally and functions as a pro-apoptotic factor by destabilizing TRAILR4 transcript. Nat Commun. 2014;5:5362.

    CAS  PubMed  Google Scholar 

  28. Leung AK, Vyas S, Rood JE, Bhutkar A, Sharp PA, Chang P. Poly(ADP-ribose) regulates stress responses and microRNA activity in the cytoplasm. Mol Cell. 2011;42:489–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Kischkel FC, Lawrence DA, Chuntharapai A, Schow P, Kim KJ, Ashkenazi A. Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity. 2000;12:611–20.

    CAS  PubMed  Google Scholar 

  30. Sprick MR, Weigand MA, Rieser E, Rauch CT, Juo P, Blenis J, et al. FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2. Immunity. 2000;12:599–609.

    CAS  PubMed  Google Scholar 

  31. Marsters SA, Sheridan JP, Pitti RM, Huang A, Skubatch M, Baldwin D, et al. A novel receptor for Apo2L/TRAIL contains a truncated death domain. Curr Biol. 1997;7:1003–6.

    CAS  PubMed  Google Scholar 

  32. Merino D, Lalaoui N, Morizot A, Schneider P, Solary E, Micheau O. Differential inhibition of TRAIL-mediated DR5-DISC formation by decoy receptors 1 and 2. Mol Cell Biol. 2006;26:7046–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Cancer Genome Atlas N. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–7.

    Google Scholar 

  34. Moser AR, Pitot HC, Dove WF. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science. 1990;247:322–4.

    CAS  PubMed  Google Scholar 

  35. Su LK, Kinzler KW, Vogelstein B, Preisinger AC, Moser AR, Luongo C, et al. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science. 1992;256:668–70.

    CAS  PubMed  Google Scholar 

  36. Spranger S, Gajewski TF. Impact of oncogenic pathways on evasion of antitumour immune responses. Nat Rev Cancer. 2018;18:139–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Smyth MJ, Takeda K, Hayakawa Y, Peschon JJ, van den Brink MR, Yagita H. Nature’s TRAIL-on a path to cancer immunotherapy. Immunity. 2003;18:1–6.

    CAS  PubMed  Google Scholar 

  38. von Karstedt S, Montinaro A, Walczak H. Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy. Nat Rev Cancer. 2017;17:352–66.

    Google Scholar 

  39. Saito Y, Nakaoka T, Sakai K, Muramatsu T, Toshimitsu K, Kimura M, et al. Inhibition of DNA methylation suppresses intestinal tumor organoids by inducing an anti-viral response. Sci Rep. 2016;6:25311.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang X, Ao H, Song M, Bai L, He W, Wang C, et al. Identification of DNA methylation regulated novel host genes relevant to inhibition of virus replication in porcine PK15 cell using double stranded RNA mimics and DNA methyltransferase inhibitor. Genomics. 2019;111:1464–73.

  41. Charron G, Li MM, MacDonald MR, Hang HC. Prenylome profiling reveals S-farnesylation is crucial for membrane targeting and antiviral activity of ZAP long-isoform. Proc Natl Acad Sci USA. 2013;110:11085–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Li S, Zhu M, Pan R, Fang T, Cao YY, Chen S, et al. The tumor suppressor PTEN has a critical role in antiviral innate immunity. Nat Immunol. 2016;17:241–9.

    CAS  PubMed  Google Scholar 

  43. Vyas S, Chesarone-Cataldo M, Todorova T, Huang YH, Chang P. A systematic analysis of the PARP protein family identifies new functions critical for cell physiology. Nat Commun. 2013;4:2240.

    PubMed  Google Scholar 

  44. Chen S, Xu Y, Zhang K, Wang X, Sun J, Gao G, et al. Structure of N-terminal domain of ZAP indicates how a zinc-finger protein recognizes complex RNA. Nat Struct Mol Biol. 2012;19:430–5.

    CAS  PubMed  Google Scholar 

  45. Huang Z, Wang X, Gao G. Analyses of SELEX-derived ZAP-binding RNA aptamers suggest that the binding specificity is determined by both structure and sequence of the RNA. Protein Cell. 2010;1:752–9.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We acknowledge Prof. Liang Chen and Prof. Tiebang Kang for helps and suggestions to this work. This work was supported by grants from the National Natural Science Foundation of China (No. 81902809 No. 81872886, No. 81773751 No. 81872887, No. 81973342, and No. 81973347), the Fundamental Research Funds for the Central Universities (and No. 18ykpy37), and the National Major Scientific and Technological Special Project for “Significant New Drugs Development” during the 13th Five-Year Plan Period (No. 2018ZXO9733002).

Funding

JC: the National Natural Science Foundation of China (No. 81902809) and the Fundamental Research Funds for the Central Universities (No. 18ykpy37). WZ: the National Natural Science Foundation of China (No. 81872886). JH: the National Natural Science Foundation of China (No. 81773751). JL: the National Natural Science Foundation of China (No. 81973342). YL: the National Natural Science Foundation of China (No. 81973347). GY: the National Natural Science Foundation of China (No. 81872887) and the National Major Scientific and Technological Special Project for “Significant New Drugs Development” during the 13th Five-Year Plan Period (No. 2018ZXO9733002).

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Authors and Affiliations

  1. Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China

    Jing Cai, Wenfeng Liu, Chun Wa Wong, Wenbo Zhu, Yuan Lin, Jun Hu, Jia Dan, Jiayu Zhang, Yang Liu, Li Guo, Zhen Qin, Xincheng Liu, Guangmei Yan & Jiankai Liang

  2. Guangzhou Virotech Pharmaceutical Co., Ltd, Guangzhou, 510663, China

    Wencang Xu, Jifu Zhang & Max Sander

  3. Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China

    Zhuo Wang

  4. Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China

    Ying Liu

  5. Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, 92093, USA

    Sihan Wu

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  1. Jing Cai
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Contributions

Conceptualization, JC, JKL and GMY; Methodology, JC, SHW and WFL; Software, XCL; Validation, WCX and JFZ; Investigation, JC, JYZ, ZQ, LG, JD, YL, YL and CWW; Resources, ZW; Writing-Original Draft, JC and JKL; Writing-Review & Editing, GMY, SHW, MS and YL; Supervision, GMY and JKL; Funding Acquisition, JC, WBZ, YL, JH, JKL and GMY.

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Correspondence to Sihan Wu or Jiankai Liang.

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Conflict of interest

W.C.X., J.F.Z., and M.S. are employers of Guangzhou Virotech Pharmaceutical Co., Ltd (GVP) and performed the animal experiment and manuscript editing. The present research is not funded by GVP. The authors declare no potential conflicts of interest.

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Cai, J., Liu, W., Wong, C.W. et al. Zinc-finger antiviral protein acts as a tumor suppressor in colorectal cancer. Oncogene 39, 5995–6008 (2020). https://doi.org/10.1038/s41388-020-01416-7

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