Abstract

Arginine methylation is considered to be one of the most permanent and one of the most frequent post-translational modifications. The reaction of transferring a methyl group from S-adenosylmethionine to arginine residue is catalyzed by aginine methyltransferase (PRMT). In humans there are nine members of the PRMT family, named in order of discovery of PRMT1- PRMT9. Arginine methyltransferases were divided into three classes: I, II, III, with regard to the product of the catalyzed reaction. The products of their activity are, respectively, the following: asymmetric dimethylarginine (ADMA), symmetrical dimethylarginine (SDMA) and monomethylarginine (MMA). These modifications significantly affect the chromatin functions; therefore, they can act as co-activators or suppressors of the transcription process. Arginine methylation plays a crucial role in many biological processes in a human organism. Among others, it participates in signal transduction control, mRNA splicing and the regulation of basic cellular processes such as proliferation, differentiation, migration and apoptosis. There is increasing evidence that dysregulation of PRMT levels may lead to the cancer transformation of cells. The correlation between increased PRMT level and cancer has been demonstrated in the following: breast, ovary, lung and colorectal cancer. The activity of arginine methyltransferase can be regulated by small molecule PRMT inhibitors. To date, three substances that inhibit PRMT activity have been evaluated in clinical trials and exhibit anti-tumor activity against hematological cancer. It is believed that the use of specific PRMT inhibitors may become a new, effective and safe treatment of oncological diseases.

References

• 1. Alam H., Gu B., Lee M.G.: Histone methylation modifiersin cellular signaling pathways. Cell. Mol. Life Sci., 2015;72: 4577–4592
  Google Scholar
• 2. Amano Y., Matsubara D., Yoshimoto T., Tamura T.,Nishino H., Mori Y., Niki T.: Expression of protein argininemethyltransferase-5 in oral squamous cell carcinoma andits significance in epithelial-to-mesenchymal transition.Pathol. Int., 2018; 68: 359–366
  Google Scholar
• 3. Baldwin R.M., Bejide M., Trinkle-Mulcahy L., Côté J.:Identification of the PRMT1v1 and PRMT1v2 specificinteractomes by quantitative mass spectrometry in breastcancer cells. Proteomics, 2015; 15: 2187–2197
  Google Scholar
• 4. Baldwin R.M., Haghandish N., Daneshmand M., AminS., Paris G., Falls T.J., Bell J.C., Islam S., Côté J.: Proteinarginine methyltransferase 7 promotes breast cancercell invasion through the induction of MMP9 expression.Oncotarget, 2015; 6: 3013–3032
  Google Scholar
• 5. Banasavadi-Siddegowda Y.K., Welker A.M., An M., YangX., Zhou W., Shi G., Imitola J., Li C., Hsu S., Wang J., PhelpsM., Zhang J., Beattie C.E., Baiocchi R., Kaur B.: PRMT5 asa druggable target for glioblastoma therapy. Neuro Oncol.,2018; 20: 753–763
  Google Scholar
• 6. Bedford M.T.: The family of protein arginine methyltransferases.The Enzymes, 2006; 24: 31–50
  Google Scholar
• 7. Behera A.K., Kumar M., Shanmugam M.K., BhattacharyaA., Rao V.J., Bhat A., Vasudevan M., Gopinath K.S.,Mohiyuddin A., Chatteriee A., Sethi G., Kundu T.K.: Functionalinterplay between YY1 and CARM1 promotes oralcarcinogenesis. Oncotarget, 2019; 10: 3709–3724
  Google Scholar
• 8. Brehmer D., Wu T., Mannens G., Beke L., Vinken P.,Gaffney D., Sun W., Pande V., Thuring J.W., Millar H., PoggesiI., Somers I., Boeckx A., Parade M., van Heerde E. iwsp.: Abstract DDT02-04: A novel PRMT5 inhibitor withpotent in vitro and in vivo activity in preclinical lung cancermodels. Cancer Res., 2017; 77: DDT02–04
  Google Scholar
• 9. Carlson S.M., Gozani O.: Emerging technologies tomap the protein methylome. J. Mol. Biol. 2014; 426:3350–3362
  Google Scholar
• 10. Carr S.M., Roworth A.P., Chan C., La Thangue N.B.:Post-translational control of transcription factors: Methylationranks highly. FEBS J., 2015; 282: 4450–4465
  Google Scholar
• 11. Castellano S., Milite C., Ragno R., Simeoni S., MaiA., Limongeli V., Novellino E., Bauer I., Brosh G., SpannhoffA., Cheng D., Bedford M.T., Sbardella G.: Design,synthesis and biological evaluation of carboxy analoguesof argininę methyltransferase inhibitor 1 (AMI-1). ChemMedChem., 2010; 5: 398–414
  Google Scholar
• 12. Cheng D., Yadav N., King R.W., Swanson M.S., WeinsteinE.J., Bedford M.T.: Small molecule regulators ofprotein arginine methyltransferases. J. Biol. Chem., 2004;279: 23892–23899
  Google Scholar
• 13. Eram M.S., Shen Y., Szewczyk M., Wu H., SenisterraG., Li F., Butler K.V., Kaniskan H.Ü., Speed B.A., Dela SeñaC., Dong A., Zeng H., Schapira M., Brown P.J., ArrowsmithC.H. i wsp.: A potent, selective, and cell-active inhibitorof human type I protein arginine methyltransferases.ACS Chem. Biol., 2016; 11: 772–781
  Google Scholar
• 14. Feng Y., Xie N., Wu J., Yang C., Zheng Y.G.: Inhibitorystudy of protein arginine methyltransferase 1 usinga fluorescent approach. Biochem. Biophys. Res. Commun.,2009; 379: 567–572
  Google Scholar
• 15. Fulton M.D., Brown T., Zheng Y.G.: Mechanisms andinhibitors of histone arginine methylation. Chem. Rec.,2018; 18: 1792–1807
  Google Scholar
• 16. Geng P., Zhang Y., Liu X., Zhang N., Liu Y., Liu X., LinC., Yan X., Li Z., Wang G., Li Y., Tan J., Liu D.X., Huang B., LuJ.: Automethylation of protein arginine methyltransferase 7 and its impact on breast cancer progression. FASEB J.,2017; 31: 2287–2300
  Google Scholar
• 17. Hadjikyriacou A., Yang Y., Espejo A., Bedford M.T.,Clarke S.G.: Unique features of human protein argininemethyltransferase 9 (PRMT9) and its substrate RNAsplicing factor SF3B2. J. Biol. Chem., 2015; 290: 16723–16743
  Google Scholar
• 18. Haghandish N., Baldwin R.M., Morettin A., Dawit H.T.,Adhikary H., Masson J.Y., Mazroui R., Trinkle-Mulcahy L.,Côté J.: PRMT7 methylates eukaryotic translation initiationfactor 2α and regulates its role in stress granule formation.Mol. Biol. Cell, 2019; 30: 778–793
  Google Scholar
• 19. Han H.S., Choi D., Choi S., Koo S.H.: Roles of proteinarginine methyltransferases in the control of glucosemetabolism. Endocrinol. Metab., 2014; 29: 435–440
  Google Scholar
• 20. Hernandez S., Dominko T.: Novel protein argininemethyltransferase 8 isoform is essential for cell proliferation.J. Cell Biochem., 2016; 117: 2056–2066
  Google Scholar
• 21. Hernandez S.J., Dolivo D.M., Dominko T.: PRMT8 demonstratesvariant-specific expression in cancer cells and correlates with patient survival in breast, ovarian andgastric cancer. Oncol. Lett., 2017; 13: 1938–1989
  Google Scholar
• 22. Hsu M.C., Pan M.R., Chu P.Y., Tsai Y.L., Tsai C.H., ShanY.S., Chen L.T., Hung W.C.: Protein arginine methyltransferase 3 enhances chemoresistance in pancreatic cancerby methylating hnRNPA1 to increase ABCG2 expression.Cancers, 2018; 11: 8
  Google Scholar
• 23. Hu G., Wang X., Han Y., Wang P.: Protein argininemethyltransferase 5 promotes bladder cancer growththrough inhibiting NF-kB dependent apoptosis. EXCLI J.,2018; 17: 1157–1166
  Google Scholar
• 24. Hu H., Qian K., Ho M.C., Zheng Y.G.: Small moleculeinhibitors of protein arginine methyltransferases. ExpertOpin. Investig. Drugs, 2016; 25: 335–358
  Google Scholar
• 25. Iderzorig T., Kellen J., Osude C., Singh S., WoodmanJ.A., Garcia C., Puri N.: Comparison of EMT mediatedtyrosine kinase inhibitor resistance in NSCLC. Biochem.Biophys. Res. Commun., 2018; 496: 770–777
  Google Scholar
• 26. Jahan S., Davie J.R.: Protein arginine methyltransferases(PRMTs): Role in chromatin organization. Adv.Biol. Regul., 2015; 57: 173–184
  Google Scholar
• 27. Kaniskan H.Ü., Eram M.S., Liu J., Smil D., Martini M.L.,Shen Y., Santhakumar V., Brown P.J., Arrowsmith C.H.,Vedadi M., Jin J.: Design and synthesis of selective, smallmolecule inhibitors od coactivator-associated argininemethyltransferase 1 (CARM1). Med. Chem. Commun.,2016; 7: 1793–1796
  Google Scholar
• 28. Karkhanis V., Hu Y.J., Baiocchi R.A., Imbalzano A.N., SifS.: Versatility of PRMT5-induced methylation in growthcontrol and development. Trends. Biochem. Sci., 2011; 36:633–641
  Google Scholar
• 29. Kleinschmidt M.A., de Graaf P., van Teeffeln H.A., TimmersH.T.: Cell cycle regulation by the PRMT6 argininemethyltransferase through repression of cyclin-dependentkinase inhibitors. PLoS One, 2012; 7: e41446
  Google Scholar
• 30. Lattouf H., Poulard C., Le Romancer M.: PRMT5 prognosticvalue in cancer. Oncotarget, 2019; 10: 3151–3153
  Google Scholar
• 31. Leipold A., Heß J., Zaoui K.: Das Epigenoom. Zielstrukturfür innovative Therapiekonzepte beim Kopf- und Halskarzinom.HNO, 2015; 63: 786–791
  Google Scholar
• 32. Li M., An W., Xu L., Lin Y., Su L., Liu X.: The argininemethyl transferase PRMT5 and PRMT1 distinctly regulatethe degradation of anti-apoptotic protein CFLARL in humanlung cancer cells. J. Exp. Clin. Cancer Res., 2019; 38: 64
  Google Scholar
• 33. Li S., Cheng D., Zhu B., Yang Q.: The overexpressionof CARM1 promotes human osteosarcoma cell proliferationthrough the pGSK3β/β-catenin/cyclinD1 signalingpathway. Int. J. Biol. Sci., 2017; 13: 976–984
  Google Scholar
• 34. Li X., Wang C., Jiang H., Luo C.: A patent review ofarginine methyltransferase inhibitors (2010–2018). ExpertOpin. Ther. Pat., 2019; 29: 97–114
  Google Scholar
• 35. Li Y., Zhu R., Wang W., Fu D., Hou J., Ji S., Chen B., HuZ., Shao X., Yu X., Zhao Q., Zhang B., Du C., Bu Q., Hu C. iwsp.: Arginine methyltransferase 1 in the nucleus accumbensregulates behavioral effects of cocaine. J. Neurosci.,2015; 35: 12890–12902
  Google Scholar
• 36. Lin H., Wang B., Yu J., Wang J., Li Q., Cao B.: Proteinarginine methyl transferase 8 gene enhances the coloncancer stem cell (CSC) function by upregulating the pluripotencytranscription factor. J. Cancer, 2018; 9: 1394–1402
  Google Scholar
• 37. Litt M., Qiu Y., Huang S.: Histone arginine methylations:Their roles in chromatin dynamics and transcriptionalregulation. Biosci. Rep., 2009; 29: 131–141
  Google Scholar
• 38. Mann M., Zou Y., Chen Y., Brann D., Vadlamudi R.:PELP1 oncogenic functions involve alternative splicingvia PRMT6. Mol. Oncol., 2014; 8: 389–400
  Google Scholar
• 39. Michalak E.M., Visvader J.E.: Dysregulation of histonemethyltransferases in breast cancer – opportunities fornew targeted therapies? Mol. Oncol., 2016; 10: 1497–1515
  Google Scholar
• 40. Nakai K., Xia W., Liao H.W., Saito M., Hung M.C., YamaguchiH.: The role of PRMT1 in EGFR methylation andsignaling in MDA-MB-468 triple-negative breast cancercells. Breast Cancer, 2018; 25: 74–80
  Google Scholar
• 41. Nakakido M., Deng Z., Suzuki T., Dohmae N., NakamuraY., Hamamoto R.: PRMT6 increases cytoplasmiclocalization of p21CDKN1A in cancer cells through argininemethylation and makes more resistant to cytotoxicagents. Oncotarget, 2015; 6: 30957–30967
  Google Scholar
• 42. Nakayama K., Szewczyk M.M., Dela Sena C., Wu H.,Dong A., Zeng H., Li F., de Freitas R.F., Eram M.S., SchapiraM., Baba Y., Kunitomo M., Cary D.R., Tawada M., OhashiA. i wsp.: TP-064, a potent and selective small moleculeinhibitor of PRMT4 for multiple myeloma. Oncotarget,2018; 9: 18480–18493
  Google Scholar
• 43. Obianyo O., Causey C.P., Jones J.E., Thompson P.R.:Activity-based protein profiling of protein arginine methyltransferase 1 ACS Chem. Biol., 2011; 6: 1127–1135
  Google Scholar
• 44. Pawlicka K., Perrigue P., Barciszewski J.: Epigenetycznakontrola procesów komórkowych. Nauka, 2018; 2:115–128
  Google Scholar
• 45. Peng C., Wong C.C.: The story of protein argininemethylation: Characterization, regulation, and function.Expert Rev. Proteomics, 2017; 14: 157–170
  Google Scholar
• 46. Poulard C., Corbo L., Le Romancer M.: Protein argininemethylation/demethylation and cancer. Oncotarget,2016; 7: 67532–67550
  Google Scholar
• 47. Prabhu L., Chen L., Wei H., Demir Ö., Safa A., Zeng L.,Amaro R.E., O’Neil B.H., Zhang Z.Y., Lu T.: Developmentof an AlphaLISA high throughput technique to screenfor small molecule inhibitors targeting protein argininemethyltransferases. Mol. Biosyst., 2017; 13: 2509–2520
  Google Scholar
• 48. Ran T., Li W., Peng B., Xie B., Lu T., Lu S., Liu W.: Virtualscreening with a structure-based pharmacophore modelto identify small-molecule inhibitors of CARM1. J. Chem.Inf. Model., 2019; 59: 522–534
  Google Scholar
• 49. Ryu J.W., Kim S.K., Son M.Y., Jeon S.J., Oh J.H., LimJ.H., Cho S., Jung C.R., Hamamoto R., Kim D.S., Cho H.S.:Novel prognostic marker PRMT1 regulates cell growth viadownregulation of CDKN1A in HCC. Oncotarget, 2017; 8:115444–115455
  Google Scholar
• 50. Shailesh H., Zakaria Z.Z., Baiocchi R., Sif S.: Proteinarginine methyltransferase 5 (PRMT5) dysregulation incancer. Oncotarget, 2018; 9: 36705–36718
  Google Scholar
• 51. Shen Y., Zhong J., Liu J., Liu K., Zhao J., Xu T., ZengT., Li Z., Chen Y., Ding W., Wen G., Zu X., Cao R.: Proteinarginine N-methyltransferase 2 reverses tamoxifen resistancein breast cancer cells through suppression of ER-α36.Oncol. Rep., 2018; 39: 2604–2612
  Google Scholar
• 52. Smith E., Zhou W., Shindiapina P., Sif S., Li C., BaiocchiR.A.: Recent advances in targeting protein arginine methyltransferaseenzymes in cancer therapy. Expert Opin.Ther. Targets, 2018; 22: 527–545
  Google Scholar
• 53. Stopa N., Krebs J.E., Shechter D.: The PRMT5 argininemethyl transferase: Many roles in development, cancerand beyond. Cell Mol. Life. Sci., 2015; 72: 2041–2059
  Google Scholar
• 54. Tewary S.K., Zheng Y.G., Ho M.C.: Protein argininemethyltransferases: Insights into the enzyme structureand mechanism at the atomic level. Cell. Mol. Life Sci.,2019; 76: 2917–2932
  Google Scholar
• 55. Vhuiyan M., Thomas D., Hossen F., Frankel A.: Targetingprotein arginine N-methyltransferases with peptidebasedinhibitors: Opportunities and challenges. FutureMed. Chem., 2013; 5: 2199–2206
  Google Scholar
• 56. Wang S.M., Dowhan D.H., Muscat G.E.: Epigeneticarginine methylation in breast cancer: Emerging therapeuticstrategies. J. Mol. Endocrinol., 2019; 62: R223–R237
  Google Scholar
• 57. Wang W.J., Hsu J.M., Wang Y.N., Lee H.H., YamaguchiH., Liao H.W., Hung M.C.: An essential role of PRMT1-mediatedEGFR methylation in EGFR activation by ribonuclease 5 Am. J. Cancer Res., 2019; 9: 180–185
  Google Scholar
• 58. Wang Y.P., Zhou W., Wang J., Hung X., Zuo Y., WangT.S., Gao X., Xu Y.Y., Zou S.W., Liu Y.B., Cheng J.K., Lei Q.Y.:Arginine methylation of MDH1 by CARM1 inhibits glutaminemetabolism and suppresses pancreatic cancer.Mol. Cell, 2016; 64: 673–687
  Google Scholar
• 59. Webb L.M., Amici S.A., Jablonski K.A., Savardekar H.,Panfil A.R., Li L., Zhou W., Peine K., Karkhanis V., BachelderE.M., Ainslie K.M., Green P.L., Li C., Baiocchi R.A., Guerau-de-Arellano M.: PRMT5-selective inhibitors suppress inflammatoryT cell responses and experimental autoimmuneencephalomyelitis. J. Immunol., 2017; 198:1439–1451
  Google Scholar
• 60. Ye F., Zhang W., Ye F., Zhang W., Ye X., Jin J., Lv Z.,Luo C.: Identification of selective, cell active inhibitors ofprotein arginine methyltransferase 5 through structurebasedvirtual screening and biological assays. J. Chem. Inf.Model., 2018; 58: 1066–1073
  Google Scholar
• 61. Ye Y., Zhang B., Mao R., Zhang C., Wang Y., Xing J.,Liu Y.C., Luo X., Ding H., Yang Y., Zhou B., Jiang H., ChenK., Luo C., Zheng M.: Discovery and optimization of selectiveinhibitors of protein arginine methyltransferase 5 by docking-based virtual screening. Org. Biomol. Chem.,2017; 15: 3648–3661
  Google Scholar
• 62. Yost J.M., Korboukh I., Liu F., Gao C., Jin J.: Targets inepigenetics: Inhibiting the methyl writers of the histonecode. Curr. Chem. Genomics, 2011; 5: 72–84
  Google Scholar
• 63. Zhang B., Chen X., Ge S., Peng C., Zhang S., Chen X.,Liu T., Zhang W.: Arginine methyltransferase inhibitor-1inhibits sarcoma viability in vitro and in vivo. Oncol. Lett.,2018; 16: 2161– 2166
  Google Scholar
• 64. Zhang B., Zhang S., Zhu L., Chen X., Zhao Y., Chao L., ZhouJ., Wang X., Zhang X., Ma N.: Arginine methyltransferase inhibitor 1 inhibits gastric cancer by downregulating eIF4E and targetingPRMT5. Toxicol. Appl. Pharmacol., 2017; 336: 1–7
  Google Scholar
• 65. Zhao X., Zhou D., Liu Y., Li C., Zhao X., Li Y., Li W.: Ganodermalucidum polysaccharide inhibits prostate cancercell migration via the protein arginine methyltransferase 6 signaling pathway. Mol. Med. Rep., 2018; 17: 147–157
  Google Scholar
• 66. Zhao Y., Lu Q., Li C., Wang X., Jiang L., Huang L., WangC., Chen H.: PRMT1 regulates the tumour-initiating propertiesof esophageal squamous cell carcinoma throughhistone H4 arginine methylation coupled with transcriptionalactivation. Cell Death. Dis., 2019; 10: 359
  Google Scholar
• 67. Zhong J., Cao R.X., Hong T., Yang J., Zu X.Y., Xiao X.H.,Liu J.H., Wen G.B.: Identification and expression analysisof a novel transcript of the human PRMT2 gene resultedfrom alternative polyadenylation in breast cancer. Gene,2011; 487: 1–9
  Google Scholar
• 68. Zhong J., Cao R.X., Liu J.H., Liu Y.B., Wang J., Liu L.P.,Chen Y.J., Yang J., Zhang Q.H., Wu Y., Ding W.J., Hong T.,Xiao X.H., Zu X.Y., Wen G.B.: Nuclear loss of protein arginineN-methyltransferase 2 in breast carcinoma is associatedwith tumor grade and overexpression of cyclin D1protein. Oncogene, 2014; 33: 5546–5558
  Google Scholar
• 69. Zhong J., Chen Y.J., Chen L., Shen Y.Y., Zhang Q.H.,Yang J., Cao R.X., Zu X.Y., Wen G.B.: PRMT2β, a C-terminalsplice variant of PRMT2β, inhibits the growth of breastcancer cells. Oncol. Rep., 2017, 38: 1303–1311
  Google Scholar
• 70. Zhong X.Y., Yuan X.M., Xu Y.Y., Yin M., Yan W.W., ZouS.W., Wei L.M., Lu H.J., Wang Y.P., Lei Q.Y.: CARM1 methylatesGAPDH to regulate glucose metabolism and is suppressedin liver cancer. Cell. Rep., 2018; 24: 3207–3223
  Google Scholar
• 71. Zhu K., Jiang C., Tao H., Liu J., Zhang H., Luo C.: Identificationof a novel selective small-molecule inhibitor ofprotein arginine methyltransferase 5 (PRMT5) by virtualscreening, resynthesis and biological evaluations. Bioorg.Med. Chem. Lett., 2018; 28: 1476–1483
  Google Scholar

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