Tumor Biology

, Volume 37, Issue 1, pp 601–610 | Cite as

Myocyte enhancer factor 2D promotes tumorigenicity in malignant glioma cells

  • Youguang Zhao
  • Ying Li
  • Yuan Ma
  • Songtao Wang
  • Jingmin Cheng
  • Tao Yang
  • Zhiyong Sun
  • Yongqin Kuang
  • Haidong Huang
  • Kexia Fan
  • Jianwen Gu
Original Article
First Online:
Received:
Accepted:

Abstract

The prognosis of patients with malignant glioma is always quite poor, and this poor prognosis is probably due to our incomplete understanding of the molecular mechanisms underlying malignant glioma. It is known that myocyte enhancer factor-2D (MEF2D) plays an oncogenic role in hepatocellular carcinoma and promotes the survival of various types of cells. However, little is known about the expression profile and function of MEF2D in malignant glioma. In this study, we investigated the function and expression of MEF2D in malignant glioma. We found that in malignant glioma, there is an aberrantly high expression of MEF2D, which leads to poor prognosis of malignant glioma. The downregulation of MEF2D suppresses the proliferation of malignant glioma cell lines by inducing delay of S and G2/M phases of cell cycle and promoting apoptosis. Furthermore, the overexpression of MEF2D in astrocytes accelerates cell proliferation by regulating cell cycle progression. Furthermore, a mouse malignant glioma model demonstrated that MEF2D deficiency blocks malignant glioma formation in vivo. We conclude that MEF2D may act as a potential oncogene in malignant glioma and thus serve as a candidate target for malignant glioma therapy.

Keywords

MEF2D Malignant glioma Cell cycle Apoptosis 
This is a preview of subscription content, log in to check access.

Supplementary material

13277_2015_3791_MOESM1_ESM.docx (20 kb)
Table S1 The relationship between MEF2D expression profiling and WHO grading, IDH 1/2 mutation, histological classification. The relationship between MEF2D expression profiling and WHO Grading based on the data from qRT-PCR and histological staining. The correlation was determined with Spearman’s rho. The relationship between MEF2D expression profiling and IDH 1/2 mutation based on the data from qRT-PCR and PCR-HRM. The correlation was determined with Spearman’s rho. The relationship between patients’ glioma histological classification and MEF2D status based on the data from histological staining and qRT-PCR. The correlation was determined with Spearman’s rho. (DOCX 20 kb)

References

  1. 1.
    Grossman SA, Ye X, Piantadosi S, Desideri S, Nabors LB, Rosenfeld M, et al. Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States. Clin Cancer Res. 2010;16(8):2443–9. doi: 10.1158/1078-0432.CCR-09-3106.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Mao Z, Bonni A, Xia F, Nadal-Vicens M, Greenberg ME. Neuronal activity-dependent cell survival mediated by transcription factor MEF2. Science. 1999;286(5440):785–90.CrossRefPubMedGoogle Scholar
  3. 3.
    Okamoto S, Krainc D, Sherman K, Lipton SA. Antiapoptotic role of the p38 mitogen-activated protein kinase-myocyte enhancer factor 2 transcription factor pathway during neuronal differentiation. Proc Natl Acad Sci U S A. 2000;97(13):7561–6. doi: 10.1073/pnas.130502697.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Olson EN, Perry M, Schulz RA. Regulation of muscle differentiation by the MEF2 family of MADS box transcription factors. Dev Biol. 1995;172(1):2–14. doi: 10.1006/dbio.1995.0002.CrossRefPubMedGoogle Scholar
  5. 5.
    Ornatsky OI, McDermott JC. MEF2 protein expression, DNA binding specificity and complex composition, and transcriptional activity in muscle and non-muscle cells. J Biol Chem. 1996;271(40):24927–33.CrossRefPubMedGoogle Scholar
  6. 6.
    Yang Q, She H, Gearing M, Colla E, Lee M, Shacka JJ, et al. Regulation of neuronal survival factor MEF2D by chaperone-mediated autophagy. Science. 2009;323(5910):124–7. doi: 10.1126/science.1166088.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Prima V, Hunger SP. Cooperative transformation by MEF2D/DAZAP1 and DAZAP1/MEF2D fusion proteins generated by the variant t (1;19) in acute lymphoblastic leukemia. Leukemia. 2007;21(12):2470–5. doi: 10.1038/sj.leu.2404962.CrossRefPubMedGoogle Scholar
  8. 8.
    Prima V, Gore L, Caires A, Boomer T, Yoshinari M, Imaizumi M, et al. Cloning and functional characterization of MEF2D/DAZAP1 and DAZAP1/MEF2D fusion proteins created by a variant t (1;19) (q23;p13.3) in acute lymphoblastic leukemia. Leukemia. 2005;19(5):806–13. doi: 10.1038/sj.leu.2403684.CrossRefPubMedGoogle Scholar
  9. 9.
    Yuki Y, Imoto I, Imaizumi M, Hibi S, Kaneko Y, Amagasa T, et al. Identification of a novel fusion gene in a pre-B acute lymphoblastic leukemia with t (1;19) (q23;p13). Cancer Sci. 2004;95(6):503–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Ma L, Liu J, Liu L, Duan G, Wang Q, Xu Y, et al. Overexpression of the transcription factor MEF2D in hepatocellular carcinoma sustains malignant character by suppressing G2-M transition genes. Cancer Res. 2014;74(5):1452–62. doi: 10.1158/0008-5472.CAN-13-2171.CrossRefPubMedGoogle Scholar
  11. 11.
    Kahali B, Gramling SJ, Marquez SB, Thompson K, Lu L, Reisman D. Identifying targets for the restoration and reactivation of BRM. Oncogene. 2014;33(5):653–64. doi: 10.1038/onc.2012.613.CrossRefPubMedGoogle Scholar
  12. 12.
    Shao J, Zhang J, Zhang Z, Jiang H, Lou X, Huang B, et al. Alternative polyadenylation in glioblastoma multiforme and changes in predicted RNA binding protein profiles. OMICS. 2013;17(3):136–49. doi: 10.1089/omi.2012.0098.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Voronova A, Al Madhoun A, Fischer A, Shelton M, Karamboulas C, Skerjanc IS. Gli2 and MEF2C activate each other’s expression and function synergistically during cardiomyogenesis in vitro. Nucleic Acids Res. 2012;40(8):3329–47. doi: 10.1093/nar/gkr1232.CrossRefPubMedGoogle Scholar
  14. 14.
    Bo Y, Guo G, Yao W. MiRNA-mediated tumor specific delivery of TRAIL reduced glioma growth. J Neuro-Oncol. 2013;112(1):27–37. doi: 10.1007/s11060-012-1033-y.CrossRefGoogle Scholar
  15. 15.
    Wales S, Hashemi S, Blais A, McDermott JC. Global MEF2 target gene analysis in cardiac and skeletal muscle reveals novel regulation of DUSP6 by p38MAPK-MEF2 signaling. Nucleic Acids Res. 2015;42(18):11349–62. doi: 10.1093/nar/gku813.CrossRefGoogle Scholar
  16. 16.
    Breitbart RE, Liang CS, Smoot LB, Laheru DA, Mahdavi V, Nadal-Ginard B. A fourth human MEF2 transcription factor, hMEF2D, is an early marker of the myogenic lineage. Development. 1993;118(4):1095–106.PubMedGoogle Scholar
  17. 17.
    Singh RK, Xia Z, Bland CS, Kalsotra A, Scavuzzo MA, Curk T, et al. Rbfox2-coordinated alternative splicing of Mef2d and Rock2 controls myoblast fusion during myogenesis. Mol Cell. 2014;55(4):592–603. doi: 10.1016/j.molcel.2014.06.035.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Lin HY, Tang HY, Shih A, Keating T, Cao G, Davis PJ, et al. Thyroid hormone is a MAPK-dependent growth factor for thyroid cancer cells and is anti-apoptotic. Steroids. 2007;72(2):180–7. doi: 10.1016/j.steroids.2006.11.014.CrossRefPubMedGoogle Scholar
  19. 19.
    Beurel E, Jope RS. The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways. Prog Neurobiol. 2006;79(4):173–89. doi: 10.1016/j.pneurobio.2006.07.006.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Ahn J, Lee H, Kim S, Park J, Ha T. The anti-obesity effect of quercetin is mediated by the AMPK and MAPK signaling pathways. Biochem Biophys Res Commun. 2008;373(4):545–9. doi: 10.1016/j.bbrc.2008.06.077.CrossRefPubMedGoogle Scholar
  21. 21.
    Reuter S, Eifes S, Dicato M, Aggarwal BB, Diederich M. Modulation of anti-apoptotic and survival pathways by curcumin as a strategy to induce apoptosis in cancer cells. Biochem Pharmacol. 2008;76(11):1340–51. doi: 10.1016/j.bcp.2008.07.031.CrossRefPubMedGoogle Scholar
  22. 22.
    Akhtar MW, Kim MS, Adachi M, Morris MJ, Qi X, Richardson JA, et al. In vivo analysis of MEF2 transcription factors in synapse regulation and neuronal survival. PLoS One. 2012;7(4):e34863. doi: 10.1371/journal.pone.0034863.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Skerjanc IS, Wilton S. Myocyte enhancer factor 2C upregulates MASH-1 expression and induces neurogenesis in P19 cells. FEBS Lett. 2000;472(1):53–6.CrossRefPubMedGoogle Scholar
  24. 24.
    Hayashi M, Kim SW, Imanaka-Yoshida K, Yoshida T, Abel ED, Eliceiri B, et al. Targeted deletion of BMK1/ERK5 in adult mice perturbs vascular integrity and leads to endothelial failure. J Clin Invest. 2004;113(8):1138–48. doi: 10.1172/JCI19890.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Olson EN. Undermining the endothelium by ablation of MAPK-MEF2 signaling. J Clin Invest. 2004;113(8):1110–2. doi: 10.1172/JCI21497.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Vitucci M, Karpinich NO, Bash RE, Werneke AM, Schmid RS, White KK, et al. Cooperativity between MAPK and PI3K signaling activation is required for glioblastoma pathogenesis. Neuro-Oncology. 2013;15(10):1317–29. doi: 10.1093/neuonc/not084.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Blau L, Knirsh R, Ben-Dror I, Oren S, Kuphal S, Hau P, et al. Aberrant expression of c-Jun in glioblastoma by internal ribosome entry site (IRES)-mediated translational activation. Proc Natl Acad Sci U S A. 2012;109(42):E2875–84. doi: 10.1073/pnas.1203659109.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Gu C, Banasavadi-Siddegowda YK, Joshi K, Nakamura Y, Kurt H, Gupta S, et al. Tumor-specific activation of the C-JUN/MELK pathway regulates glioma stem cell growth in a p53-dependent manner. Stem Cells. 2013;31(5):870–81. doi: 10.1002/stem.1322.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol. 2008;116(6):597–602. doi: 10.1007/s00401-008-0455-2.CrossRefPubMedGoogle Scholar
  30. 30.
    Bleeker FE, Lamba S, Leenstra S, Troost D, Hulsebos T, Vandertop WP, et al. IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors. Hum Mutat. 2009;30(1):7–11. doi: 10.1002/humu.20937.CrossRefPubMedGoogle Scholar
  31. 31.
    Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360(8):765–73. doi: 10.1056/NEJMoa0808710.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Ma L, Liu J, Shen J, Liu L, Wu J, Li W, et al. Expression of miR-122 mediated by adenoviral vector induces apoptosis and cell cycle arrest of cancer cells. Cancer Biol Ther. 2010;9(7):554–61.CrossRefPubMedGoogle Scholar
  33. 33.
    Wang B, Wang H, Yang Z. MiR-122 inhibits cell proliferation and tumorigenesis of breast cancer by targeting IGF1R. PLoS One. 2012;7(10):e47053. doi: 10.1371/journal.pone.0047053.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Qian J, Zhai A, Kao W, Li Y, Song W, Fu Y, et al. Modulation of miR-122 on persistently Borna disease virus infected human oligodendroglial cells. Antivir Res. 2010;87(2):249–56. doi: 10.1016/j.antiviral.2010.05.011.CrossRefPubMedGoogle Scholar
  35. 35.
    Wang G, Zhao Y, Zheng Y. MiR-122/Wnt/beta-catenin regulatory circuitry sustains glioma progression. Tumour Biol. 2014;35(9):8565–72. doi: 10.1007/s13277-014-2089-4.CrossRefPubMedGoogle Scholar
  36. 36.
    Kim MK, Kim SC, Kang JI, Hyun JH, Boo HJ, Eun SY, et al. 6-Hydroxydopamine-induced PC12 cell death is mediated by MEF2D down-regulation. Neurochem Res. 2011;36(2):223–31. doi: 10.1007/s11064-010-0309-x.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Youguang Zhao
    • 1
    • 2
  • Ying Li
    • 3
  • Yuan Ma
    • 4
  • Songtao Wang
    • 5
  • Jingmin Cheng
    • 4
  • Tao Yang
    • 4
  • Zhiyong Sun
    • 4
  • Yongqin Kuang
    • 4
  • Haidong Huang
    • 4
  • Kexia Fan
    • 4
  • Jianwen Gu
    • 4
    • 6
  1. 1.Department of PostgraduateThird Military Medical UniversityChongqingPeople’s Republic of China
  2. 2.Department of UrologyChengdu Military General HospitalChengduPeople’s Republic of China
  3. 3.Department of CardiologyChengdu Military General HospitalChengduPeople’s Republic of China
  4. 4.Department of NeurosurgeryChengdu Military General HospitalChengduPeople’s Republic of China
  5. 5.Section of Scientific Research and TrainingChengdu Military General HospitalChengduPeople’s Republic of China
  6. 6.The 306th Hospital of PLABeijingPeople’s Republic of China

Personalised recommendations