Skip to main content

Advertisement

SpringerLink
Log in

Expression of PRMT5 correlates with malignant grade in gliomas and plays a pivotal role in tumor growth in vitro

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Protein arginine methyltransferase 5 (PRMT5) catalyzes the formation of ω-NG,N′G-symmetric dimethylarginine residues on histones as well as other proteins. These modifications play an important role in cell differentiation and tumor cell growth. However, the role of PRMT5 in human glioma cells has not been characterized. In this study, we assessed protein expression profiles of PRMT5 in control brain, WHO grade II astrocytomas, anaplastic astrocytomas, and glioblastoma multiforme (GBM) by immunohistochemistry. PRMT5 was low in glial cells in control brain tissues and low grade astrocytomas. Its expression increased in parallel with malignant progression, and was highly expressed in GBM. Knockdown of PRMT5 by small hairpin RNA caused alterations of p-ERK1/2 and significantly repressed the clonogenic potential and viability of glioma cells. These findings indicate that PRMT5 is a marker of malignant progression in glioma tumors and plays a pivotal role in tumor growth.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Yang Y, Bedford MT (2013) Protein arginine methyltransferases and cancer. Nat Rev 13(1):37–50

    Article  CAS  Google Scholar 

  2. Friesen WJ, Paushkin S, Wyce A et al (2001) The methylosome, a 20S complex containing JBP1 and pICln, produces dimethylarginine-modified Sm proteins. Mol Cell Biol 21(24):8289–8300

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Hsu JM, Chen CT, Chou CK et al (2011) Crosstalk between Arg 1175 methylation and Tyr 1173 phosphorylation negatively modulates EGFR-mediated ERK activation. Nat Cell Biol 13(2):174–181

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Jansson M, Durant ST, Cho EC et al (2008) Arginine methylation regulates the p53 response. Nat Cell Biol 10(12):1431–1439

    Article  CAS  PubMed  Google Scholar 

  5. Teng Y, Girvan AC, Casson LK et al (2007) AS1411 alters the localization of a complex containing protein arginine methyltransferase 5 and nucleolin. Cancer Res 67(21):10491–10500

    Article  CAS  PubMed  Google Scholar 

  6. Scoumanne A, Zhang J, Chen X (2009) PRMT5 is required for cell-cycle progression and p53 tumor suppressor function. Nucleic Acids Res 37(15):4965–4976

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Andreu-Perez P, Esteve-Puig R, Esteve-Puig R, de Torre-Minguela C et al (2011) Protein arginine methyltransferase 5 regulates ERK1/2 signal transduction amplitude and cell fate through CRAF. Sci Signal 4(190):ra58

    Article  PubMed  Google Scholar 

  8. Pal S, Baiocchi RA, Byrd JC et al (2007) Low levels of miR-92b/96 induce PRMT5 translation and H3R8/H4R3 methylation in mantle cell lymphoma. EMBO J 26(15):3558–3569

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Wang L, Pal S, Sif S (2008) Protein arginine methyltransferase 5 suppresses the transcription of the RB family of tumor suppressors in leukemia and lymphoma cells. Mol Cell Biol 28(20):6262–6277

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Kim JM, Sohn HY, Yoon SY et al (2005) Identification of gastric cancer-related genes using a cDNA microarray containing novel expressed sequence tags expressed in gastric cancer cells. Clin Cancer Res 11(2 Pt 1):473–482

    PubMed  Google Scholar 

  11. Eckert D, Biermann K, Nettersheim D et al (2008) Expression of BLIMP1/PRMT5 and concurrent histone H2A/H4 arginine 3 dimethylation in fetal germ cells, CIS/IGCNU and germ cell tumors. BMC Dev Biol 8:106

    Article  PubMed Central  PubMed  Google Scholar 

  12. Powers MA, Fay MM, Factor RE et al (2011) Protein arginine methyltransferase 5 accelerates tumor growth by arginine methylation of the tumor suppressor programmed cell death 4. Cancer Res 71(16):5579–5587

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Bao X, Zhao S, Liu T et al (2013) Overexpression of PRMT5 promotes tumor cell growth and is associated with poor disease prognosis in epithelial ovarian cancer. J Histochem Cytochem 61(3):206–217

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Tanaka H, Hoshikawa Y, Oh-hara T et al (2009) PRMT5, a novel TRAIL receptor-binding protein, inhibits TRAIL-induced apoptosis via nuclear factor-kappaB activation. Mol Cancer Res 7(4):557–569

    Article  CAS  PubMed  Google Scholar 

  15. Yang M, Sun J, Sun X et al (2009) Caenorhabditis elegans protein arginine methyltransferase PRMT-5 negatively regulates DNA damage-induced apoptosis. PLoS Genet 5(6):e1000514

    Article  PubMed Central  PubMed  Google Scholar 

  16. Aggarwal P, Vaites LP, Kim JK et al (2010) Nuclear cyclin D1/CDK4 kinase regulates CUL4 expression and triggers neoplastic growth via activation of the PRMT5 methyltransferase. Cancer Cell 18(4):329–340

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Pal S, Vishwanath SN, Erdjument-Bromage H, Tempst P, Sif S (2004) Human SWI/SNF-associated PRMT5 methylates histone H3 arginine 8 and negatively regulates expression of ST7 and NM23 tumor suppressor genes. Mol Cell Biol 24(21):9630–9645

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Tee WW, Pardo M, Theunissen TW et al (2010) PRMT5 is essential for early mouse development and acts in the cytoplasm to maintain ES cell pluripotency. Genes Dev 24(24):2772–2777

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Chittka A (2010) Dynamic distribution of histone H4 arginine 3 methylation marks in the developing murine cortex. PLoS One 5(11):e13807

    Article  PubMed Central  PubMed  Google Scholar 

  20. Chittka A, Nitarska J, Grazini U, Richardson WD (2012) Transcription factor positive regulatory domain 4 (PRDM4) recruits protein arginine methyltransferase 5 (PRMT5) to mediate histone arginine methylation and control neural stem cell proliferation and differentiation. J Biol Chem 287(51):42995–43006

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Jemal A, Murray T, Samuels A et al (2003) Cancer statistics, 2003. CA Cancer J Clin 53(1):5–26

    Article  PubMed  Google Scholar 

  22. Ohgaki H, Kleihues P (2005) Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 64(6):479–489

    CAS  PubMed  Google Scholar 

  23. Tran B, Rosenthal MA (2010) Survival comparison between glioblastoma multiforme and other incurable cancers. J Clin Neurosci 17(4):417–421

    Article  CAS  PubMed  Google Scholar 

  24. Ishibashi H, Suzuki T, Suzuki S et al (2003) Sex steroid hormone receptors in human thymoma. J Clin Endocrinol Metab 88(5):2309–2317

    Article  CAS  PubMed  Google Scholar 

  25. Robertson D, Savage K, Reis-Filho JS, Isacke CM (2008) Multiple immunofluorescence labelling of formalin-fixed paraffin-embedded (FFPE) tissue. BMC Cell Biol 9:13

    Article  PubMed Central  PubMed  Google Scholar 

  26. Inai T, Mancuso M, Hashizume H et al (2004) Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol 165(1):35–52

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Wiederschain D, Wee S, Chen L et al (2009) Single-vector inducible lentiviral RNAi system for oncology target validation. Cell Cycle 8(3):498–504

    Article  CAS  PubMed  Google Scholar 

  28. Han X, Stewart JE Jr, Bellis SL et al (2001) TGF-beta1 up-regulates paxillin protein expression in malignant astrocytoma cells: requirement for a fibronectin substrate. Oncogene 20(55):7976–7986

    Article  CAS  PubMed  Google Scholar 

  29. Karkhanis V, Hu YJ, Baiocchi RA et al (2011) Versatility of PRMT5-induced methylation in growth control and development. Trends Biochem Sci 36(12):633–641

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Lee JH, Cook JR, Yang ZH et al (2005) PRMT7, a new protein arginine methyltransferase that synthesizes symmetric dimethylarginine. J Biol Chem 280(5):3656–3664

    Article  CAS  PubMed  Google Scholar 

  31. Zhao Q, Rank G, Tan YT et al (2009) PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing. Nat Struct Mol Biol 16(3):304–311

    Article  CAS  PubMed  Google Scholar 

  32. Ancelin K, Lange UC, Hajkova P et al (2006) Blimp1 associates with Prmt5 and directs histone arginine methylation in mouse germ cells. Nat Cell Biol 8(6):623–630

    Article  CAS  PubMed  Google Scholar 

  33. Bedford MT, Clarke SG (2009) Protein arginine methylation in mammals: who, what, and why. Mol Cell 33(1):1–13

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Huang J, Vogel G, Yu Z, Almazan G, Richard S (2011) Type II arginine methyltransferase PRMT5 regulates gene expression of inhibitors of differentiation/DNA binding Id2 and Id4 during glial cell differentiation. J Biol Chem 286(52):44424–44432

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Friedmann-Morvinski D, Bushong EA, Ke E et al (2012) Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science 338(6110):1080–1084

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Dunn GP, Rinne ML, Wykosky J et al (2012) Emerging insights into the molecular and cellular basis of glioblastoma. Genes Dev 26(8):756–784

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Verhaak RG, Hoadley KA, Purdom E et al (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17(1):98–110

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Krakstad C, Chekenya M (2010) Survival signalling and apoptosis resistance in glioblastomas: opportunities for targeted therapeutics. Mol Cancer 9:135

    Article  PubMed Central  PubMed  Google Scholar 

  39. Marshall CJ (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80(2):179–185

    Article  CAS  PubMed  Google Scholar 

  40. Olsen BB, Svenstrup TH, Guerra B (2012) Downregulation of protein kinase CK2 induces autophagic cell death through modulation of the mTOR and MAPK signaling pathways in human glioblastoma cells. Int J Oncol 41(6):1967–1976

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Pang L, Sawada T, Decker SJ, Saltiel AR (1995) Inhibition of MAP kinase kinase blocks the differentiation of PC-12 cells induced by nerve growth factor. J Biol Chem 270(23):13585–13588

    Article  CAS  PubMed  Google Scholar 

  42. Ravi RK, Weber E, McMahon M et al (1998) Activated Raf-1 causes growth arrest in human small cell lung cancer cells. J Clin Investig 101(1):153–159

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Cho EC, Zheng S, Munro S et al (2012) Arginine methylation controls growth regulation by E2F-1. EMBO J 31(7):1785–1797

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

NIH NCI Grants P30CA013148 (UAB Comprehensive Cancer Center Core Support Grant); P50CA097247, P20CA151129 (G. Y. Gillespie); St. Baldrick’s Foundation (G. K. Friedman); VA Merit Review (P. H. King).

Conflict of interest

None of the authors has a conflict of interest to declare.

Author information

Authors and Affiliations

  1. Department of Neurology, The University of Alabama at Birmingham, FOT 1020, 1530 3rd Ave S, Birmingham, AL, 35294-3410, USA

    Xiaosi Han, Wenbin Zhang, Xiuhua Yang, Crystal G. Wheeler, Paula Province, Hassan M. Fathallah-Shaykh, Peter H. King & L. Burt Nabors

  2. Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, 35294-3410, USA

    Rong Li

  3. Division of Hematology/Oncology, Department of Pediatrics, The University of Alabama at Birmingham, Birmingham, AL, 35294-3410, USA

    Gregory K. Friedman

  4. Division of Pulmonary Medicine, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, 35294-3410, USA

    Qiang Ding

  5. Department of Preventive Medicine, The University of Alabama at Birmingham, Birmingham, AL, 35294-3410, USA

    Zhiying You

  6. Department of Neurosurgery, The University of Alabama at Birmingham, Birmingham, AL, 35294-3410, USA

    G. Yancey Gillespie

  7. Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL, 35294-3410, USA

    Xinyang Zhao

  8. Birmingham Veterans Affairs Medical Center, Birmingham, AL, 35295, USA

    Xiaosi Han & Peter H. King

Authors
  1. Xiaosi Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wenbin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiuhua Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Crystal G. Wheeler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gregory K. Friedman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Paula Province
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qiang Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zhiying You
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hassan M. Fathallah-Shaykh
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. G. Yancey Gillespie
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xinyang Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Peter H. King
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. L. Burt Nabors
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiaosi Han.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Han, X., Li, R., Zhang, W. et al. Expression of PRMT5 correlates with malignant grade in gliomas and plays a pivotal role in tumor growth in vitro. J Neurooncol 118, 61–72 (2014). https://doi.org/10.1007/s11060-014-1419-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-014-1419-0

Keywords

Search

Navigation