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RNA Editing Enzyme ADAR1 Suppresses the Mobility of Cancer Cells via ARPIN

  • Min Ji Park (Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Eunji Jeong (Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Eun Ji Lee (Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Hyeon Ji Choi (Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Bo Hyun Moon (Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Keunsoo Kang (Department of Microbiology, College of Science & Technology, Dankook University Korea) ;
  • Suhwan Chang (Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine)
  • Received : 2022.11.09
  • Accepted : 2023.01.15
  • Published : 2023.06.30

Abstract

Deamination of adenine or cytosine in RNA, called RNA editing, is a constitutively active and common modification. The primary role of RNA editing is tagging RNA right after its synthesis so that the endogenous RNA is recognized as self and distinguished from exogenous RNA, such as viral RNA. In addition to this primary function, the direct or indirect effects on gene expression can be utilized in cancer where a high level of RNA editing activity persists. This report identified actin-related protein 2/3 complex inhibitor (ARPIN) as a target of ADAR1 in breast cancer cells. Our comparative RNA sequencing analysis in MCF7 cells revealed that the expression of ARPIN was decreased upon ADAR1 depletion with altered editing on its 3'UTR. However, the expression changes of ARPIN were not dependent on 3'UTR editing but relied on three microRNAs acting on ARPIN. As a result, we found that the migration and invasion of cancer cells were profoundly increased by ADAR1 depletion, and this cellular phenotype was reversed by the exogenous ARPIN expression. Altogether, our data suggest that ADAR1 suppresses breast cancer cell mobility via the upregulation of ARPIN.

Keywords

Acknowledgement

This study was supported by the National Research Foundation of Korea (NRF2021R1 A6A1A03040260, NRF2021R1A2C2005472) and Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (KHI-DIHI21C00710).

References

  1. Athanasiadis, A., Rich, A., and Maas, S. (2004). Widespread A-to-I RNA editing of Alu-containing mRNAs in the human transcriptome. PLoS Biol. 2, e391.
  2. Baker, A.R. and Slack, F.J. (2022). ADAR1 and its implications in cancer development and treatment. Trends Genet. 38, 821-830. https://doi.org/10.1016/j.tig.2022.03.013
  3. Chang, S. and Sharan, S.K. (2012). BRCA1 and microRNAs: emerging networks and potential therapeutic targets. Mol. Cells 34, 425-432. https://doi.org/10.1007/s10059-012-0118-y
  4. Chen, L., Li, Y., Lin, C.H., Chan, T.H., Chow, R.K., Song, Y., Liu, M., Yuan, Y.F., Fu, L., Kong, K.L., et al. (2013). Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma. Nat. Med. 19, 209-216. https://doi.org/10.1038/nm.3043
  5. Cho, C.J., Jung, J., Jiang, L., Lee, E.J., Kim, D.S., Kim, B.S., Kim, H.S., Jung, H.Y., Song, H.J., Hwang, S.W., et al. (2018). Combinatory RNA-sequencing analyses reveal a dual mode of gene regulation by ADAR1 in gastric cancer. Dig. Dis. Sci. 63, 1835-1850. https://doi.org/10.1007/s10620-018-5081-9
  6. Danan-Gotthold, M., Guyon, C., Giraud, M., Levanon, E.Y., and Abramson, J. (2016). Extensive RNA editing and splicing increase immune self-representation diversity in medullary thymic epithelial cells. Genome Biol. 17, 219.
  7. Dang, I., Gorelik, R., Sousa-Blin, C., Derivery, E., Guerin, C., Linkner, J., Nemethova, M., Dumortier, J.G., Giger, F.A., Chipysheva, T.A., et al. (2013). Inhibitory signalling to the Arp2/3 complex steers cell migration. Nature 503, 281-284. https://doi.org/10.1038/nature12611
  8. Daniel, C., Silberberg, G., Behm, M., and Ohman, M. (2014). Alu elements shape the primate transcriptome by cis-regulation of RNA editing. Genome Biol. 15, R28.
  9. Gallo, A., Vukic, D., Michalik, D., O'Connell, M.A., and Keegan, L.P. (2017). ADAR RNA editing in human disease; more to it than meets the I. Hum. Genet. 136, 1265-1278. https://doi.org/10.1007/s00439-017-1837-0
  10. Ishizuka, J.J., Manguso, R.T., Cheruiyot, C.K., Bi, K., Panda, A., Iracheta-Vellve, A., Miller, B.C., Du, P.P., Yates, K.B., Dubrot, J., et al. (2019). Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade. Nature 565, 43-48. https://doi.org/10.1038/s41586-018-0768-9
  11. Iwaya, K., Norio, K., and Mukai, K. (2007). Coexpression of Arp2 and WAVE2 predicts poor outcome in invasive breast carcinoma. Mod. Pathol. 20, 339-343. https://doi.org/10.1038/modpathol.3800741
  12. Izdebska, M., Zielinska, W., Halas-Wisniewska, M., and Grzanka, A. (2020). Involvement of actin and actin-binding proteins in carcinogenesis. Cells 9, 2245.
  13. Jiang, L., Park, M.J., Cho, C.J., Lee, K., Jung, M.K., Pack, C.G., Myung, S.J., and Chang, S. (2020). ADAR1 suppresses interferon signaling in gastric cancer cells by microRNA-302a-mediated IRF9/STAT1 regulation. Int. J. Mol. Sci. 21, 6195.
  14. Kashani-Sabet, M., Rangel, J., Torabian, S., Nosrati, M., Simko, J., Jablons, D.M., Moore, D.H., Haqq, C., Miller, J.R., 3rd, and Sagebiel, R.W. (2009). A multi-marker assay to distinguish malignant melanomas from benign nevi. Proc. Natl. Acad. Sci. U. S. A. 106, 6268-6272. https://doi.org/10.1073/pnas.0901185106
  15. Kim, H.R., Kwon, M.S., Lee, S., Mun, Y., Lee, K.S., Kim, C.H., Na, B.R., Kim, B.N.R., Piragyte, I., Lee, H.S., et al. (2018). TAGLN2 polymerizes G-actin in a low ionic state but blocks Arp2/3-nucleated actin branching in physiological conditions. Sci. Rep. 8, 5503.
  16. Kono, M. and Akiyama, M. (2019). Dyschromatosis symmetrica hereditaria and reticulate acropigmentation of Kitamura: an update. J. Dermatol. Sci. 93, 75-81. https://doi.org/10.1016/j.jdermsci.2019.01.004
  17. Kung, C.P., Cottrell, K.A., Ryu, S., Bramel, E.R., Kladney, R.D., Bao, E.A., Freeman, E.C., Sabloak, T., Maggi, L., Jr., and Weber, J.D. (2021). Evaluating the therapeutic potential of ADAR1 inhibition for triple-negative breast cancer. Oncogene 40, 189-202. https://doi.org/10.1038/s41388-020-01515-5
  18. Lamers, M.M., van den Hoogen, B.G., and Haagmans, B.L. (2019). ADAR1: "editor-in-chief" of cytoplasmic innate immunity. Front. Immunol. 10, 1763.
  19. Lazzari, E., Mondala, P.K., Santos, N.D., Miller, A.C., Pineda, G., Jiang, Q., Leu, H., Ali, S.A., Ganesan, A.P., Wu, C.N., et al. (2017). Alu-dependent RNA editing of GLI1 promotes malignant regeneration in multiple myeloma. Nat. Commun. 8, 1922.
  20. Li, Y., Qiu, J., Pang, T., Guo, Z., Su, Y., Zeng, Q., and Zhang, X. (2017). Restoration of Arpin suppresses aggressive phenotype of breast cancer cells. Biomed. Pharmacother. 92, 116-121. https://doi.org/10.1016/j.biopha.2017.05.053
  21. Liu, Z., Yang, X., Chen, C., Liu, B., Ren, B., Wang, L., Zhao, K., Yu, S., and Ming, H. (2013). Expression of the Arp2/3 complex in human gliomas and its role in the migration and invasion of glioma cells. Oncol. Rep. 30, 2127-2136. https://doi.org/10.3892/or.2013.2669
  22. Livak, K.J. and Schmittgen, T.D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25, 402-408. https://doi.org/10.1006/meth.2001.1262
  23. Livingston, J.H., Lin, J.P., Dale, R.C., Gill, D., Brogan, P., Munnich, A., Kurian, M.A., Gonzalez-Martinez, V., De Goede, C.G., Falconer, A., et al. (2014). A type I interferon signature identifies bilateral striatal necrosis due to mutations in ADAR1. J. Med. Genet. 51, 76-82. https://doi.org/10.1136/jmedgenet-2013-102038
  24. Lomakina, M.E., Lallemand, F., Vacher, S., Molinie, N., Dang, I., Cacheux, W., Chipysheva, T.A., Ermilova, V.D., de Koning, L., Dubois, T., et al. (2016). Arpin downregulation in breast cancer is associated with poor prognosis. Br. J. Cancer 114, 545-553. https://doi.org/10.1038/bjc.2016.18
  25. Mehdipour, P., Marhon, S.A., Ettayebi, I., Chakravarthy, A., Hosseini, A., Wang, Y., de Castro, F.A., Loo Yau, H., Ishak, C., Abelson, S., et al. (2020). Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency. Nature 588, 169-173. https://doi.org/10.1038/s41586-020-2844-1
  26. Nemlich, Y., Baruch, E.N., Besser, M.J., Shoshan, E., Bar-Eli, M., Anafi, L., Barshack, I., Schachter, J., Ortenberg, R., and Markel, G. (2018). ADAR1-mediated regulation of melanoma invasion. Nat. Commun. 9, 2154.
  27. Nemlich, Y., Greenberg, E., Ortenberg, R., Besser, M.J., Barshack, I., Jacob-Hirsch, J., Jacoby, E., Eyal, E., Rivkin, L., Prieto, V.G., et al. (2013). MicroRNA-mediated loss of ADAR1 in metastatic melanoma promotes tumor growth. J. Clin. Invest. 123, 2703-2718. https://doi.org/10.1172/JCI62980
  28. Ota, H., Sakurai, M., Gupta, R., Valente, L., Wulff, B.E., Ariyoshi, K., Iizasa, H., Davuluri, R.V., and Nishikura, K. (2013). ADAR1 forms a complex with Dicer to promote microRNA processing and RNA-induced gene silencing. Cell 153, 575-589. https://doi.org/10.1016/j.cell.2013.03.024
  29. Quin, J., Sedmik, J., Vukic, D., Khan, A., Keegan, L.P., and O'Connell, M.A. (2021). ADAR RNA modifications, the epitranscriptome and innate immunity. Trends Biochem. Sci. 46, 758-771. https://doi.org/10.1016/j.tibs.2021.02.002
  30. Rice, G.I., Kasher, P.R., Forte, G.M., Mannion, N.M., Greenwood, S.M., Szynkiewicz, M., Dickerson, J.E., Bhaskar, S.S., Zampini, M., Briggs, T.A., et al. (2012). Mutations in ADAR1 cause Aicardi-Goutieres syndrome associated with a type I interferon signature. Nat. Genet. 44, 1243-1248. https://doi.org/10.1038/ng.2414
  31. Riedmann, E.M., Schopoff, S., Hartner, J.C., and Jantsch, M.F. (2008). Specificity of ADAR-mediated RNA editing in newly identified targets. RNA 14, 1110-1118. https://doi.org/10.1261/rna.923308
  32. Rotty, J.D., Wu, C., and Bear, J.E. (2013). New insights into the regulation and cellular functions of the ARP2/3 complex. Nat. Rev. Mol. Cell Biol. 14, 7-12. https://doi.org/10.1038/nrm3492
  33. Shigeyasu, K., Okugawa, Y., Toden, S., Miyoshi, J., Toiyama, Y., Nagasaka, T., Takahashi, N., Kusunoki, M., Takayama, T., Yamada, Y., et al. (2018). AZIN1 RNA editing confers cancer stemness and enhances oncogenic potential in colorectal cancer. JCI Insight 3, e99976.
  34. Shoshan, E., Mobley, A.K., Braeuer, R.R., Kamiya, T., Huang, L., Vasquez, M.E., Salameh, A., Lee, H.J., Kim, S.J., Ivan, C., et al. (2015). Reduced adenosine-to-inosine miR-455-5p editing promotes melanoma growth and metastasis. Nat. Cell Biol. 17, 311-321. https://doi.org/10.1038/ncb3110
  35. Suzuki, N., Suzuki, T., Inagaki, K., Ito, S., Kono, M., Fukai, K., Takama, H., Sato, K., Ishikawa, O., Abe, M., et al. (2005). Mutation analysis of the ADAR1 gene in dyschromatosis symmetrica hereditaria and genetic differentiation from both dyschromatosis universalis hereditaria and acropigmentatio reticularis. J. Invest. Dermatol. 124, 1186-1192. https://doi.org/10.1111/j.0022-202X.2005.23732.x
  36. Takeda, S., Shigeyasu, K., Okugawa, Y., Yoshida, K., Mori, Y., Yano, S., Noma, K., Umeda, Y., Kondo, Y., Kishimoto, H., et al. (2019). Activation of AZIN1 RNA editing is a novel mechanism that promotes invasive potential of cancer-associated fibroblasts in colorectal cancer. Cancer Lett. 444, 127-135. https://doi.org/10.1016/j.canlet.2018.12.009
  37. Veltman, D. (2014). Actin dynamics: cell migration takes a new turn with arpin. Curr. Biol. 24, R31-R33. https://doi.org/10.1016/j.cub.2013.11.022
  38. Volkmann, N., Amann, K.J., Stoilova-McPhie, S., Egile, C., Winter, D.C., Hazelwood, L., Heuser, J.E., Li, R., Pollard, T.D., and Hanein, D. (2001). Structure of Arp2/3 complex in its activated state and in actin filament branch junctions. Science 293, 2456-2459. https://doi.org/10.1126/science.1063025
  39. Wang, I.X., So, E., Devlin, J.L., Zhao, Y., Wu, M., and Cheung, V.G. (2013). ADAR regulates RNA editing, transcript stability, and gene expression. Cell Rep. 5, 849-860. https://doi.org/10.1016/j.celrep.2013.10.002
  40. Yu, J., Zhang, C., Yu, Q., Yu, H., and Zhang, B. (2019). ADAR1 p110 enhances adhesion of tumor cells to extracellular matrix in hepatocellular carcinoma via up-regulating ITGA2 expression. Med. Sci. Monit. 25, 1469-1479. https://doi.org/10.12659/MSM.911944
  41. Zheng, H.C., Zheng, Y.S., Li, X.H., Takahashi, H., Hara, T., Masuda, S., Yang, X.H., Guan, Y.F., and Takano, Y. (2008). Arp2/3 overexpression contributed to pathogenesis, growth and invasion of gastric carcinoma. Anticancer Res. 28(4B), 2225-2232.