Skip to main content

Advertisement

Log in

Clinical evaluation of PRMT1 gene expression in breast cancer

  • Research Article
  • Published:
Tumor Biology

Abstract

Methylation of arginine residues has been implicated in many cellular activities like mRNA splicing, transcription regulation, signal transduction and protein–protein interactions. Protein arginine methyltransferases are the enzymes responsible for this modification in living cells. The most commonly used methyltransferase in man is protein arginine methyltransferase 1 (PRMT1). Since methylation processes appear to interfere in the emergence of several diseases, including cancer, we investigated the localisation of the protein in cancer tissue and, for the first time, the relation that possibly exists between the expression of PRMT1 gene and breast cancer progression. We used tumour specimens from 62 breast cancer patients and semi-quantitative RT-PCR to determine the expression of PRMT1 gene and was found to be associated with patient’s age (p = 0.002), menopausal status (p = 0.006), tumour grade (p = 0.03), and progesterone receptor status (p = 0.001). Survival curves revealed that PRMT1-v1 status-low expression relates to longer disease-free survival (DFS; p = 0.036). To the contrary, PRMT1-v2 status is not associated neither with the clinical or pathological parameters nor with DFS (p = 0.31). PRMT1-v3 was not statistically significantly expressed in breast cancer tissue. Selected cancer and normal breast samples were stained for PRMT1. In both normal and cancerous breast tissues, staining was in the cytoplasm and only in rare cases the cell nucleus appeared stained. Present results show a potential use for this gene as a marker of unfavourable prognosis for breast cancer patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Walsh T, King MC. Ten genes for inherited breast cancer. Cancer Cell. 2007;11:103–5.

    Article  PubMed  CAS  Google Scholar 

  2. Aletta JM, Cimato TR, Ettinger MJ. Protein methylation: a signal event in post-translational modification. Trends Biochem Sci. 1998;23:89–91.

    Article  PubMed  CAS  Google Scholar 

  3. Bedford MT, Richard S. Arginine methylation: an emerging regulator of protein function. Mol Cell. 2005;18:263–72.

    Article  PubMed  CAS  Google Scholar 

  4. Lin WJ, Gary JD, Yang MC, Clarke S, Herschman HR. The mammalian immediate-early TIS21 protein and the leukemia-associated BTG1 protein interact with a protein-arginine N-methyltransferase. J Biol Chem. 1996;271:15034–44.

    Article  PubMed  CAS  Google Scholar 

  5. Scott HS, Antonarakis SE, Lalioti MD, Rossier C, Silver PA, Henry MF. Identification and characterization of two putative human arginine methyltransferases (HRMT1L1 and HRMT1L2). Genomics. 1998;48:330–40.

    Article  PubMed  CAS  Google Scholar 

  6. Tang J, Gary JD, Clarke S, Herschman HR. PRMT 3, a type I protein arginine N-methyltransferase that differs from PRMT1 in its oligomerization, subcellular localization, substrate specificity, and regulation. J Biol Chem. 1998;273:16935–45.

    Article  PubMed  CAS  Google Scholar 

  7. Chen D, Ma H, Hong H, Koh SS, Huang SM, Schurter BT, et al. Regulation of transcription by a protein methyltransferase. Science. 1999;284:2174–7.

    Article  PubMed  CAS  Google Scholar 

  8. Pollack BP, Kotenko SV, He W, Izotova LS, Barnoski BL, Pestka S. The human homologue of the yeast proteins Skb1 and Hsl7p interacts with Jak kinases and contains protein methyltransferase activity. J Biol Chem. 1999;274:31531–42.

    Article  PubMed  CAS  Google Scholar 

  9. Frankel A, Yadav N, Lee J, Branscombe TL, Clarke S, Bedford MT. The novel human protein arginine N-methyltransferase PRMT6 is a nuclear enzyme displaying unique substrate specificity. J Biol Chem. 2002;277:3537–43.

    Article  PubMed  CAS  Google Scholar 

  10. Miranda TB, Miranda M, Frankel A, Clarke S. PRMT7 is a member of the protein arginine methyltransferase family with a distinct substrate specificity. J Biol Chem. 2004;279:22902–7.

    Article  PubMed  CAS  Google Scholar 

  11. Lee J, Sayegh J, Daniel J, Clarke S, Bedford MT. PRMT8, a new membrane-bound tissue-specific member of the protein arginine methyltransferase family. J Biol Chem. 2005;280:32890–6.

    Article  PubMed  CAS  Google Scholar 

  12. Cook JR, Lee J-H, Yang Z-H, Krause CD, Herth N, Hoffmann R, et al. FBXO11/PRMT9, a new protein arginine methyltransferase, symmetrically dimethylates arginine residues. Biochem Biophys Res Commun. 2006;342:472–81.

    Article  PubMed  CAS  Google Scholar 

  13. Krause CD, Yang ZH, Kim YS, Lee JH, Cook JR, Pestka S. Protein arginine methyltransferase: evolution and assessment of their pharmacological and therapeutic potential. Pharmacol Ther. 2007;113(1):50–87.

    Article  PubMed  CAS  Google Scholar 

  14. Zobel-Thropp P, Gary JD, Clarke S. delta-N-methylarginine is a novel posttranslational modification of arginine residues in yeast proteins. J Biol Chem. 1998;273:29283–6.

    Article  PubMed  CAS  Google Scholar 

  15. Nicholson TB, Chen T, Richard S. The physiological and pathological role of PRMT1-mediated protein arginine methylation. Pharmacol Res. 2009;60:466–74.

    Article  PubMed  CAS  Google Scholar 

  16. McBride AE, Silver PA. State of the arg: protein methylation at arginine comes of age. Cell. 2001;106:5–8.

    Article  PubMed  CAS  Google Scholar 

  17. Boisvert FM, Cote J, Boulanger MC, Richard S. A proteomic analysis of arginine-methylated protein complexes. Mol Cell Proteomics. 2003;2:1319–30.

    Article  PubMed  CAS  Google Scholar 

  18. Herrmann F, Bossert M, Schwander A, Akgun E, Fackelmayer FO. Arginine methylation of scaffold attachment factor A by heterogeneous nuclear ribonucleoprotein particle-associated PRMT1. J Biol Chem. 2004;279:48774–9.

    Article  PubMed  CAS  Google Scholar 

  19. Wang H, Huang ZQ, Xia L, Feng Q, Erdjument-Bromage H, Strahl BD, et al. Methylation of histone H4 at arginine 3 facilitating transcriptional activation by nuclear hormone receptor. Science. 2001;293:853–7.

    Article  PubMed  CAS  Google Scholar 

  20. Pawlak MR, Scherer CA, Chen J, Roshon MJ, Ruley HE. Arginine N-methyltransferase 1 is required for early postimplantation mouse development, but cells deficient in the enzyme are viable. Mol Cell Biol. 2000;20:4859–69.

    Article  PubMed  CAS  Google Scholar 

  21. Najbauer J, Johnson BA, Young AL, Aswad DW. Peptides with sequences similar to glycine, arginine-rich motifs in proteins interacting with RNA are efficiently recognized by methyltransferase(s) modifying arginine in numerous proteins. J Biol Chem. 1993;268:10501–9.

    PubMed  CAS  Google Scholar 

  22. Lee DY, Teyssier C, Strahl BD, Stallcup MR. Role of protein methylation in regulation of transcription. Endocr Rev. 2005;26:147–70.

    Article  PubMed  CAS  Google Scholar 

  23. Boisvert FM, Rhie A, Richard S, Doherty AJ. The GAR motif of 53BP1 is arginine methylated by PRMT1 and is necessary for 53BP1 DNA binding activity. Cell Cycle. 2005;4:1834–41.

    Article  PubMed  CAS  Google Scholar 

  24. Scorilas A, Black MH, Talieri M, Diamandis EP. Genomic organization, physical mapping, and expression analysis of the human protein arginine methyltransferase 1 gene. Biochem Biophys Res Commun. 2000;278:349–59.

    Article  PubMed  CAS  Google Scholar 

  25. Araya N, Hiraga H, Kako K, Arao Y, Kato S, Fukamizu A. Transcriptional down-regulation through nuclear exclusion of EWS methylated by PRMT1. Biochem Biophys Res Commun. 2005;329:653–60.

    Article  PubMed  CAS  Google Scholar 

  26. Herrmann F, Lee J, Bedford MT, Fackelmayer FO. Dynamics of human protein arginine methyltransferase 1(PRMT1) in vivo. J Biol Chem. 2005;280:38005–10.

    Article  PubMed  CAS  Google Scholar 

  27. Goulet I, Gauvin G, Boisvenue S, Cote J. Alternative splicing yields PRMT1 isoforms with distinct activity, substrate specificity, and subcellular localisation. J Biol Chem. 2007;282:33009–21.

    Article  PubMed  CAS  Google Scholar 

  28. Shin DM, Chiao PJ, Sacks PG, Shin HJ, Hong WK, Hittelman WN, et al. Activation of ribosomal protein S2 gene expression in a hamster model of chemically induced oral carcinogenesis. Carcinogenesis. 1993;14:163–6.

    Article  PubMed  CAS  Google Scholar 

  29. Li C, Ai AS, Lin CH, Hsieh M, Li YC, Li SY. Protein N-arginine methylation in adenosine dialdehyde-treated lymphoblastoid cells. Arch Biochem Biophys. 1998;351:53–9.

    Article  PubMed  CAS  Google Scholar 

  30. Gu H, Park SH, Park GH, Lin IK, Lee HW, Paik WK, et al. Identification of highly methylated arginine residues in an endogenous 20-kDa polypeptide in cancer cells. Life Sci. 1999;65:737–45.

    Article  PubMed  CAS  Google Scholar 

  31. Mathioudaki K, Papadokostopoulou A, Scorilas A, Xynopoulos A, Agnanti N, Talieri M. The PRMT1 gene expression pattern in colon cancer. Br J Cancer. 2008;99(12):2094–9.

    Article  PubMed  CAS  Google Scholar 

  32. Le Romancer M, Treilleux I, Bouchekioua-Bouzaghou K, Sentis S, Corbo L. Methylation, a key step for nongenomic estrogen signaling in breast tumors. Steroids. 2010;75:560–4.

    Article  PubMed  Google Scholar 

  33. Nichols RC, Wang XW, Tang J, Hamilton BJ, High FA, Herschman HR, et al. The RGG domain in hnRNP A2 affects subcellular localization. Exp Cell Res. 2000;256:522–32.

    Article  PubMed  CAS  Google Scholar 

  34. Tang J, Kao PN, Herschman HR. Protein-arginine methyltransferase I, the predominant protein-arginine methyltransferase in cells, interacts with and is regulated by interleukin enhancer-binding factor 3. J Biol Chem. 2000;275:19866–76.

    Article  PubMed  CAS  Google Scholar 

  35. Teyssier C, Ma H, Emter R, Kralli A, Stallcup MR. Activation of nuclear receptor coactivator PGC-1alpha by arginine methylation. Genes Dev. 2005;19:1466–73.

    Article  PubMed  CAS  Google Scholar 

  36. Yager JD, Davidson NE. Estrogen carcinogenesis in breast cancer. N Engl J Med. 2006;354:270–82.

    Article  PubMed  CAS  Google Scholar 

  37. Ismail PM, Amato P, Soyal SM, DeMayo FJ, Conneely OM, O’Malley BW, et al. Progesterone involvement in breast development and tumorigenesis-as revealed by progesterone receptor “knockout” and “knockin” mouse models. Steroids. 2003;68:779–87.

    Article  PubMed  CAS  Google Scholar 

  38. Herman F, Fackelmayer FO. Nucleo-cytoplasmic shuttling of protein arginine methyltransferase 1 (PRMT1) requires enzymatic activity. Genes Cells. 2009;4:309–17.

    Article  Google Scholar 

Download references

Acknowledgement

The authors thank Mr. George Vilaras, Technologist in the Department of Pathology, 417 VA Hospital (NIMTS), Athens, Greece, for his technical assistance.

Conflicts of interest

None

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Maroulio Talieri.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mathioudaki, K., Scorilas, A., Ardavanis, A. et al. Clinical evaluation of PRMT1 gene expression in breast cancer. Tumor Biol. 32, 575–582 (2011). https://doi.org/10.1007/s13277-010-0153-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-010-0153-2

Keywords

Navigation