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Identification of the role of mono-ADP-ribosylation in colorectal cancer by integrated transcriptome analysis

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Abstract

Our previous study clarified the carcinogenic properties of arginine-specific mono-ADP-ribosyltransferase 1 (ART1), which results in a critical post-translational modification that changes the structure and function of proteins and is widely involved in important processes. This study provides, for the first time, a comprehensive transcriptomic analysis of colorectal cancer cells with ART1 silencing by Illumina RNA-Seq and related verification experiments. Lentiviral infection was used to construct a CT-26 cell line with stable knockdown of the ART1 gene, and a whole transcriptome sequencing technique was performed to identify differentially expressed genes (DEGs). GO and KEGG classification/enrichment analyses and verification experiments were performed to determine the role of ART1 in the progression of colorectal cancer. A total of 5552 DEGs, GO functions and KEGG pathways with the highest enrichment, various SNPs, and diverse splicing patterns were identified. Importantly, knockdown of ART1 affected the splicing of certain key genes related to tumor cell growth and downregulated the expression of the key gene PTBP1 for alternative splicing. The overall attenuation of the endoplasmic reticulum unfolded protein response (UPR) signaling pathway caused by the inhibition of mono-ADP-ribosylation of GRP78 could disrupt UPR signaling, leading to the occurrence of apoptosis to impede tumorigenesis. ART1, which is clustered in organelles, may promote the development of colorectal cancer by participating in a variety of new mechanisms, including endoplasmic reticulum stress regulation and alternative splicing, and may be a good clinical drug target for targeted therapy of CRC.

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Data availability

The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. https://doi.org/10.3322/caac.21492.

    Article  PubMed  Google Scholar 

  2. Butepage M, Eckei L, Verheugd P, Luscher B. Intracellular mono-ADP-ribosylation in signaling and disease. Cells. 2015;4(4):569–95. https://doi.org/10.3390/cells4040569.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Ame JC, Spenlehauer C, de Murcia G. The PARP superfamily. BioEssays. 2004;26(8):882–93. https://doi.org/10.1002/bies.20085.

    Article  CAS  PubMed  Google Scholar 

  4. Palazzo L, Mikoc A, Ahel I. ADP-ribosylation: new facets of an ancient modification. FEBS J. 2017;284(18):2932–46. https://doi.org/10.1111/febs.14078.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Kuang J, Wang YL, Xiao M, Tang Y, Chen WW, Song GL, et al. Synergistic effect of arginine-specific ADP-ribosyltransferase 1 and poly(ADP-ribose) polymerase-1 on apoptosis induced by cisplatin in CT26 cells. Oncol Rep. 2014;31(5):2335–43. https://doi.org/10.3892/or.2014.3100.

    Article  CAS  PubMed  Google Scholar 

  6. Tang Y, Wang YL, Yang L, Xu JX, Xiong W, Xiao M, et al. Inhibition of arginine ADP-ribosyltransferase 1 reduces the expression of poly(ADP-ribose) polymerase-1 in colon carcinoma. Int J Mol Med. 2013;32(1):130–6. https://doi.org/10.3892/ijmm.2013.1370.

    Article  CAS  PubMed  Google Scholar 

  7. Xiao M, Tang Y, Wang YL, Yang L, Li X, Kuang J, et al. ART1 silencing enhances apoptosis of mouse CT26 cells via the PI3K/Akt/NF-kappaB pathway. Cell Physiol Biochem. 2013;32(6):1587–99. https://doi.org/10.1159/000356595.

    Article  CAS  PubMed  Google Scholar 

  8. Yang L, Xiao M, Li X, Tang Y, Wang YL. Arginine ADP-ribosyltransferase 1 promotes angiogenesis in colorectal cancer via the PI3K/Akt pathway. Int J Mol Med. 2016;37(3):734–42. https://doi.org/10.3892/ijmm.2016.2473.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Castle JC, Loewer M, Boegel S, de Graaf J, Bender C, Tadmor AD, et al. Immunomic, genomic and transcriptomic characterization of CT26 colorectal carcinoma. BMC Genomics. 2014;15:190. https://doi.org/10.1186/1471-2164-15-190.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Bisognin A, Pizzini S, Perilli L, Esposito G, Mocellin S, Nitti D, et al. An integrative framework identifies alternative splicing events in colorectal cancer development. Mol Oncol. 2014;8(1):129–41. https://doi.org/10.1016/j.molonc.2013.10.004.

    Article  CAS  PubMed  Google Scholar 

  11. Zheng PP, Sieuwerts AM, Luider TM, van der Weiden M, Sillevis-Smitt PA, Kros JM. Differential expression of splicing variants of the human caldesmon gene (CALD1) in glioma neovascularization versus normal brain microvasculature. Am J Pathol. 2004;164(6):2217–28. https://doi.org/10.1016/S0002-9440(10)63778-9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Georgilis A, Klotz S, Hanley CJ, Herranz N, Weirich B, Morancho B, et al. PTBP1-mediated alternative splicing regulates the inflammatory secretome and the pro-tumorigenic effects of senescent cells. Cancer Cell. 2018;34(1):85-102 e9. https://doi.org/10.1016/j.ccell.2018.06.007.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Zhou L, Zhan M-L, Tang Y, Xiao M, Li M, Li Q-S, et al. Effects of β-caryophyllene on arginine ADP-ribosyltransferase 1-mediated regulation of glycolysis in colorectal cancer under high-glucose conditions. Int J Oncol. 2018. https://doi.org/10.3892/ijo.2018.4506.

    Article  PubMed Central  PubMed  Google Scholar 

  14. Fang JY, Richardson BC. The MAPK signalling pathways and colorectal cancer. Lancet Oncol. 2005;6(5):322–7. https://doi.org/10.1016/S1470-2045(05)70168-6.

    Article  CAS  PubMed  Google Scholar 

  15. Bos JL, Fearon ER, Hamilton SR, Verlaan-de Vries M, van Boom JH, van der Eb AJ, et al. Prevalence of ras gene mutations in human colorectal cancers. Nature. 1987;327(6120):293–7. https://doi.org/10.1038/327293a0.

    Article  CAS  PubMed  Google Scholar 

  16. Song GL, Jin CC, Zhao W, Tang Y, Wang YL, Li M, et al. Regulation of the RhoA/ROCK/AKT/beta-catenin pathway by arginine-specific ADP-ribosytransferases 1 promotes migration and epithelial–mesenchymal transition in colon carcinoma. Int J Oncol. 2016;49(2):646–56. https://doi.org/10.3892/ijo.2016.3539.

    Article  CAS  PubMed  Google Scholar 

  17. Xu JX, Xiong W, Zeng Z, Tang Y, Wang YL, Xiao M, et al. Effect of ART1 on the proliferation and migration of mouse colon carcinoma CT26 cells in vivo. Mol Med Rep. 2017;15(3):1222–8. https://doi.org/10.3892/mmr.2017.6152.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Oakes SA, Papa FR. The role of endoplasmic reticulum stress in human pathology. Annu Rev Pathol. 2015;10:173–94. https://doi.org/10.1146/annurev-pathol-012513-104649.

    Article  CAS  PubMed  Google Scholar 

  19. Xu C, Bailly-Maitre B, Reed JC. Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest. 2005;115(10):2656–64. https://doi.org/10.1172/JCI26373.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Corda D, Di Girolamo M. Functional aspects of protein mono-ADP-ribosylation. EMBO J. 2003;22(9):1953–8. https://doi.org/10.1093/emboj/cdg209.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Fabrizio G, Di Paola S, Stilla A, Giannotta M, Ruggiero C, Menzel S, et al. ARTC1-mediated ADP-ribosylation of GRP78/BiP: a new player in endoplasmic-reticulum stress responses. Cell Mol Life Sci. 2015;72(6):1209–25. https://doi.org/10.1007/s00018-014-1745-6.

    Article  CAS  PubMed  Google Scholar 

  22. Zhou L, Zhan ML, Tang Y, Xiao M, Li M, Li QS, et al. Effects of beta-caryophyllene on arginine ADP-ribosyltransferase 1-mediated regulation of glycolysis in colorectal cancer under high-glucose conditions. Int J Oncol. 2018;53(4):1613–24. https://doi.org/10.3892/ijo.2018.4506.

    Article  CAS  PubMed  Google Scholar 

  23. Xiao M, Tang Y, Chen WW, Wang YL, Yang L, Li X, et al. Tubb3 regulation by the Erk and Akt signaling pathways: a mechanism involved in the effect of arginine ADP-ribosyltransferase 1 (Art1) on apoptosis of colon carcinoma CT26 cells. Tumour Biol. 2016;37(2):2353–63. https://doi.org/10.1007/s13277-015-4058-y.

    Article  CAS  PubMed  Google Scholar 

  24. Paone G, Wada A, Stevens LA, Matin A, Hirayama T, Levine RL, et al. ADP ribosylation of human neutrophil peptide-1 regulates its biological properties. Proc Natl Acad Sci USA. 2002;99(12):8231–5. https://doi.org/10.1073/pnas.122238899.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Saxty BA, Yadollahi-Farsani M, Upton PD, Johnstone SR, MacDermot J. Inactivation of platelet-derived growth factor-BB following modification by ADP-ribosyltransferase. Br J Pharmacol. 2001;133(8):1219–26. https://doi.org/10.1038/sj.bjp.0704187.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Zolkiewska A, Moss J. Integrin alpha 7 as substrate for a glycosylphosphatidylinositol-anchored ADP-ribosyltransferase on the surface of skeletal muscle cells. J Biol Chem. 1993;268(34):25273–6.

    Article  CAS  PubMed  Google Scholar 

  27. Vera Alvarez R, Pongor LS, Marino-Ramirez L, Landsman D. TPMCalculator: one-step software to quantify mRNA abundance of genomic features. Bioinformatics. 2019;35(11):1960–2. https://doi.org/10.1093/bioinformatics/bty896.

    Article  CAS  PubMed  Google Scholar 

  28. Chambers JE, Petrova K, Tomba G, Vendruscolo M, Ron D. ADP ribosylation adapts an ER chaperone response to short-term fluctuations in unfolded protein load. J Cell Biol. 2012;198(3):371–85. https://doi.org/10.1083/jcb.201202005.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Ledford BE, Leno GH. ADP-ribosylation of the molecular chaperone GRP78/BiP. Mol Cell Biochem. 1994;138(1–2):141–8. https://doi.org/10.1007/BF00928456.

    Article  CAS  PubMed  Google Scholar 

  30. Clerte C, Hall KB. The domains of polypyrimidine tract binding protein have distinct RNA structural preferences. Biochemistry. 2009;48(10):2063–74. https://doi.org/10.1021/bi8016872.

    Article  CAS  PubMed  Google Scholar 

  31. Stoneley M, Willis AE. Cellular internal ribosome entry segments: structures, trans-acting factors and regulation of gene expression. Oncogene. 2004;23(18):3200–7. https://doi.org/10.1038/sj.onc.1207551.

    Article  CAS  PubMed  Google Scholar 

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Funding

The research was supported by Innovation Project of Graduate Student in Chongqing (CYB19160); National Nature Science Foundation of China (30870946); Science and Technology Research Foundation of Chongqing Municipal Education Commission (KJQN201800435).

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Authors

Contributions

SXZ and JLD processed the cell culture, RNA extraction, and analysis of the sequencing result. SXZ wrote the manuscript. YPY and HJG were responsible for the process of validation experiments. YT, MX designed and conducted the experiments. QSL, ML also participated in analysis and interpretation of data of RNA-Seq. YLW was responsible for funding acquisition and manuscript modification.

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Correspondence to Yalan Wang.

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Zhang, S., Duan, J., Yang, Y. et al. Identification of the role of mono-ADP-ribosylation in colorectal cancer by integrated transcriptome analysis. Med Oncol 38, 111 (2021). https://doi.org/10.1007/s12032-021-01559-x

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