Cell Biology and Toxicology

, Volume 34, Issue 6, pp 425–440 | Cite as

New aspects of glioblastoma multiforme revealed by similarities between neural and glioblastoma stem cells

  • Yoichiro Kawamura
  • Jun Takouda
  • Koji Yoshimoto
  • Kinichi NakashimaEmail author


Neural stem cells (NSCs) undergo self-renewal and generate neurons and glial cells under the influence of specific signals from surrounding environments. Glioblastoma multiforme (GBM) is a highly lethal brain tumor arising from NSCs or glial precursor cells owing to dysregulation of transcriptional and epigenetic networks that control self-renewal and differentiation of NSCs. Highly tumorigenic glioblastoma stem cells (GSCs) constitute a small subpopulation of GBM cells, which share several characteristic similarities with NSCs. GSCs exist atop a stem cell hierarchy and generate heterogeneous populations that participate in tumor propagation, drug resistance, and relapse. During multimodal treatment, GSCs de-differentiate and convert into cells with malignant characteristics, and thus play critical roles in tumor propagation. In contrast, differentiation therapy that induces GBM cells or GSCs to differentiate into a neuronal or glial lineage is expected to inhibit their proliferation. Since stem cell differentiation is specified by the cells’ epigenetic status, understanding their stemness and the epigenomic situation in the ancestor, NSCs, is important and expected to be helpful for developing treatment modalities for GBM. Here, we review the current findings regarding the epigenetic regulatory mechanisms of NSC fate in the developing brain, as well as those of GBM and GSCs. Furthermore, considering the similarities between NSCs and GSCs, we also discuss potential new strategies for GBM treatment.


Differentiation therapy Epigenetics Glioblastoma multiforme Glioblastoma stem cells Neural stem cells 





5-hydroxymethyl cytosine


α-ketoglutaric acid


Achaete scute homolog 1


Alpha-thalassemia/mental retardation syndrome X-linked


Basic fibroblast growth factor


bone morphogenetic protein receptor 1 B


Ciliary neurotrophic factor


DNA methyltransferases


Embryonic stem cell


Enhancer of zeste homolog 2


Substitution of glycine 34 with arginine or valine


Glioblastoma multiforme


CpG island methylator phenotype of glioma


Glioblastoma stem cell


Histone 3, lysine 9


Histone acetyltransferase


Histone deacetylase


Hox transcript antisense intergenic RNA


Isocitrate dehydrogenase 1


Induced pluripotent stem cell


Lysine methyltransferase

K27 M

Substitution of lysine 27 with methionine


Lymphoid enhancer factor


Long non-coding RNA


O6-methylguanine–DNA methyltransferase




Non-coding RNA


Neurogenic differentiation


Notch intracellular domain


Neurogenin 1


Neural stem cell


Polycomb repressor complex 1/2


Repressor element 1 silencing transcription factor


Receptor tyrosine kinase


Small C-terminal domain phosphatase 1


Signal Transducer and Activator of Transcription


T-cell factor


The Cancer Genome Atlas






Trichostatin A


Valproic acid



We apologize to colleagues whose work we may not have been able to be included in this review due to space constraints.We thank all of the members of the Laboratory of Molecular Neuroscience, Department of Stem Cell Biology and Medicine, Kyushu University, for their valuable comments, and Elizabeth Nakajima for critical reading of this manuscript. This work was supported by MEXT KAKENHI (16H06527) to K. N.


  1. Adefuin AM, Kimura A, Noguchi H, Nakashima K, Namihira M. Epigenetic mechanisms regulating differentiation of neural stem/precursor cells. Epigenomics. 2014;6:637–49.CrossRefGoogle Scholar
  2. Alelu-Paz R, Ashour N, Gonzalez-Corpas A, Ropero S. DNA methylation, histone modifications, and signal transduction pathways: a close relationship in malignant gliomas pathophysiology. J Signal Transduct. 2012;2012:956958.CrossRefGoogle Scholar
  3. Asano H, Aonuma M, Sanosaka T, Kohyama J, Namihira M, Nakashima K. Astrocyte differentiation of neural precursor cells is enhanced by retinoic acid through a change in epigenetic modification. Stem Cells. 2009;27:2744–52.CrossRefGoogle Scholar
  4. Bender S, Tang Y, Lindroth AM, Hovestadt V, Jones DT, Kool M, et al. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell. 2013;24:660–72.CrossRefGoogle Scholar
  5. Bezecny P. Histone deacetylase inhibitors in glioblastoma: pre-clinical and clinical experience. Med Oncol. 2014;31:985.CrossRefGoogle Scholar
  6. Bird A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002;16:6–21.CrossRefGoogle Scholar
  7. Bulstrode H, Johnstone E, Marques-Torrejon MA, Ferguson KM, Bressan RB, Blin C, et al. Elevated FOXG1 and SOX2 in glioblastoma enforces neural stem cell identity through transcriptional control of cell cycle and epigenetic regulators. Genes Dev. 2017;31:757–73.CrossRefGoogle Scholar
  8. Cadieux B, Ching TT, Vandenberg SR, Costello JF. Genome-wide hypomethylation in human glioblastomas associated with specific copy number alteration, methylenetetrahydrofolate reductase allele status, and increased proliferation. Cancer Res. 2006;66:8469–76.CrossRefGoogle Scholar
  9. Cancer Genome Atlas Research, N. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455:1061–8.CrossRefGoogle Scholar
  10. Caren H, Stricker SH, Bulstrode H, Gagrica S, Johnstone E, Bartlett TE, et al. Glioblastoma stem cells respond to differentiation cues but fail to undergo commitment and terminal cell-cycle arrest. Stem Cell Rep. 2015;5:829–42.CrossRefGoogle Scholar
  11. Chaboub LS, Deneen B. Astrocyte form and function in the developing central nervous system. Semin Pediatr Neurol. 2013;20:230–5.CrossRefGoogle Scholar
  12. Chen H, Li X, Li W, Zheng H. miR-130a can predict response to temozolomide in patients with glioblastoma multiforme, independently of O6-methylguanine-DNA methyltransferase. J Transl Med. 2015;13:69.CrossRefGoogle Scholar
  13. Cimmino L, Aifantis I. Alternative roles for oxidized mCs and TETs. Curr Opin Genet Dev. 2017;42:1–7.CrossRefGoogle Scholar
  14. Counts JL, Goodman JI. Alterations in DNA methylation may play a variety of roles in carcinogenesis. Cell. 1995;83:13–5.CrossRefGoogle Scholar
  15. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462:739–44.CrossRefGoogle Scholar
  16. De Santa F, Totaro MG, Prosperini E, Notarbartolo S, Testa G, Natoli G. The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell. 2007;130:1083–94.CrossRefGoogle Scholar
  17. Eckschlager T, Plch J, Stiborova M, Hrabeta J. Histone deacetylase inhibitors as anticancer drugs. Int J Mol Sci. 2017;18:E1414.CrossRefGoogle Scholar
  18. Esteller M. Non-coding RNAs in human disease. Nat Rev Genet. 2011;12:861–74.CrossRefGoogle Scholar
  19. Eyupoglu IY, Savaskan NE. Epigenetics in brain tumors: HDACs take center stage. Curr Neuropharmacol. 2016;14:48–54.CrossRefGoogle Scholar
  20. Fan X, Khaki L, Zhu TS, Soules ME, Talsma CE, Gul N, et al. NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells. 2010;28:5–16.Google Scholar
  21. Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18:553–67.CrossRefGoogle Scholar
  22. Flavahan WA, Wu Q, Hitomi M, Rahim N, Kim Y, Sloan AE, et al. Brain tumor initiating cells adapt to restricted nutrition through preferential glucose uptake. Nat Neurosci. 2013;16:1373–82.CrossRefGoogle Scholar
  23. Forrest ME, Khalil AM. Review: regulation of the cancer epigenome by long non-coding RNAs. Cancer Lett. 2017;407:106–12.CrossRefGoogle Scholar
  24. Fouse SD, Costello JF. Epigenetics of neurological cancers. Future Oncol. 2009;5:1615–29.CrossRefGoogle Scholar
  25. Furutachi S, Miya H, Watanabe T, Kawai H, Yamasaki N, Harada Y, et al. Slowly dividing neural progenitors are an embryonic origin of adult neural stem cells. Nat Neurosci. 2015;18:657–65.CrossRefGoogle Scholar
  26. Gage FH. Mammalian neural stem cells. Science. 2000;287:1433–8.CrossRefGoogle Scholar
  27. Greer EL, Shi Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet. 2012;13:343–57.CrossRefGoogle Scholar
  28. Hahn MA, Qiu R, Wu X, Li AX, Zhang H, Wang J, et al. Dynamics of 5-hydroxymethylcytosine and chromatin marks in mammalian neurogenesis. Cell Rep. 2013;3:291–300.CrossRefGoogle Scholar
  29. Hegi ME, Diserens A-C, Gorlia T, Hamou M-F, De Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352:997–1003.CrossRefGoogle Scholar
  30. Hirabayashi Y, Gotoh Y. Epigenetic control of neural precursor cell fate during development. Nat Rev Neurosci. 2010;11:377–88.CrossRefGoogle Scholar
  31. Hitoshi S, Seaberg RM, Koscik C, Alexson T, Kusunoki S, Kanazawa I, et al. Primitive neural stem cells from the mammalian epiblast differentiate to definitive neural stem cells under the control of notch signaling. Genes Dev. 2004;18:1806–11.CrossRefGoogle Scholar
  32. Hitoshi S, Ishino Y, Kumar A, Jasmine S, Tanaka KF, Kondo T, et al. Mammalian Gcm genes induce Hes5 expression by active DNA demethylation and induce neural stem cells. Nat Neurosci. 2011;14(8):957–64.CrossRefGoogle Scholar
  33. Hsieh J, Nakashima K, Kuwabara T, Mejia E, Gage FH. Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells. Proc Natl Acad Sci U S A. 2004;101:16659–64.CrossRefGoogle Scholar
  34. Hu B, Wang Q, Wang YA, Hua S, Sauve CG, Ong D, et al. Epigenetic activation of WNT5A drives glioblastoma stem cell differentiation and invasive growth. Cell. 2016;167:1281–1295.e18.CrossRefGoogle Scholar
  35. Issa JP, Kantarjian HM. Targeting Dna methylation. Clin Cancer Res. 2009;15:3938–46.CrossRefGoogle Scholar
  36. Iwadate Y. Epithelial-mesenchymal transition in glioblastoma progression. Oncol Lett. 2016;11:1615–20.CrossRefGoogle Scholar
  37. Kawamura Y, Katada S, Noguchi H, Yamamoto H, Sanosaka T, Iihara K, et al. Synergistic induction of astrocytic differentiation by factors secreted from meninges in the mouse developing brain. FEBS Lett. 2017;591(22):3709–20.CrossRefGoogle Scholar
  38. Ke J, Yao YL, Zheng J, Wang P, Liu YH, Ma J, et al. Knockdown of long non-coding RNA HOTAIR inhibits malignant biological behaviors of human glioma cells via modulation of miR-326. Oncotarget. 2015;6:21934–49.Google Scholar
  39. Kondo T. Epigenetic alchemy for cell fate conversion. Curr Opin Genet Dev. 2006;16:502–7.CrossRefGoogle Scholar
  40. Kondo T, Setoguchi T, Taga T. Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci U S A. 2004;101:781–6.CrossRefGoogle Scholar
  41. Kondo Y, Katsushima K, Ohka F, Natsume A, Shinjo K. Epigenetic dysregulation in glioma. Cancer Sci. 2014;105:363–9.CrossRefGoogle Scholar
  42. Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T. Identification of tissue-specific microRNAs from mouse. Curr Biol. 2002;12:735–9.CrossRefGoogle Scholar
  43. Lan F, Bayliss PE, Rinn JL, Whetstine JR, Wang JK, Chen S, et al. A histone H3 lysine 27 demethylase regulates animal posterior development. Nature. 2007;449:689–94.CrossRefGoogle Scholar
  44. Lee KK, Workman JL. Histone acetyltransferase complexes: one size doesn't fit all. Nat Rev Mol Cell Biol. 2007;8:284–95.CrossRefGoogle Scholar
  45. Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM, et al. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell. 2006;9:391–403.CrossRefGoogle Scholar
  46. Lee J, Son MJ, Woolard K, Donin NM, Li A, Cheng CH, et al. Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell. 2008;13:69–80.CrossRefGoogle Scholar
  47. Lessard J, Wu JI, Ranish JA, Wan M, Winslow MM, Staahl BT, et al. An essential switch in subunit composition of a chromatin remodeling complex during neural development. Neuron. 2007;55(2):201–15.CrossRefGoogle Scholar
  48. Li Y, Guessous F, Zhang Y, Dipierro C, Kefas B, Johnson E, et al. MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. Cancer Res. 2009;69:7569–76.CrossRefGoogle Scholar
  49. Li D, Marchenko ND, Moll UM. SAHA shows preferential cytotoxicity in mutant p53 cancer cells by destabilizing mutant p53 through inhibition of the HDAC6-Hsp90 chaperone axis. Cell Death Differ. 2011;18:1904–13.CrossRefGoogle Scholar
  50. Liau BB, Sievers C, Donohue LK, Gillespie SM, Flavahan WA, Miller TE, et al. Adaptive chromatin remodeling drives glioblastoma stem cell plasticity and drug tolerance. Cell Stem Cell. 2017;20:233–246.e7.CrossRefGoogle Scholar
  51. Liu XS, Wu H, Ji X, Stelzer Y, Wu X, Czauderna S, et al. Editing DNA methylation in the mammalian genome. Cell. 2016;167:233–247.e17.CrossRefGoogle Scholar
  52. Lu QR, Yuk D, Alberta JA, Zhu Z, Pawlitzky I, Chan J, et al. Sonic hedgehog—regulated oligodendrocyte lineage genes encoding bHLH proteins in the mammalian central nervous system. Neuron. 2000;25:317–29.CrossRefGoogle Scholar
  53. Ma DK, Marchetto MC, Guo JU, Ming GL, Gage FH, Song H. Epigenetic choreographers of neurogenesis in the adult mammalian brain. Nat Neurosci. 2010;13:1338–44.CrossRefGoogle Scholar
  54. Mao P, Joshi K, Li J, Kim SH, Li P, Santana-Santos L, et al. Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3. PNAS. 2013;110:8644–9.CrossRefGoogle Scholar
  55. Margueron R, Reinberg D. The polycomb complex PRC2 and its mark in life. Nature. 2011;469:343–9.CrossRefGoogle Scholar
  56. Marks PA, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK. Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer. 2001;1:194–202.CrossRefGoogle Scholar
  57. Mazor T, Pankov A, Song JS, Costello JF. Intratumoral heterogeneity of the epigenome. Cancer Cell. 2016;29:440–51.CrossRefGoogle Scholar
  58. Megova M, Drabek J, Koudelakova V, Trojanec R, Kalita O, Hajduch M. Isocitrate dehydrogenase 1 and 2 mutations in gliomas. J Neurosci Res. 2014;92:1611–20.CrossRefGoogle Scholar
  59. Miller FD, Gauthier AS. Timing is everything: making neurons versus glia in the developing cortex. Neuron. 2007;54:357–69.CrossRefGoogle Scholar
  60. Morita S, Noguchi H, Horii T, Nakabayashi K, Kimura M, Okamura K, et al. Targeted DNA demethylation in vivo using dCas9-peptide repeat and scFv-TET1 catalytic domain fusions. Nat Biotechnol. 2016;34:1060–5.CrossRefGoogle Scholar
  61. Morrow T, Song MR, Fau-Ghosh A, Ghosh A. Sequential specification of neurons and glia by developmentally regulated extracellular factors. Development. 2001;128(18):3585–94.Google Scholar
  62. Murata H, Yoshimoto K, Hatae R, Akagi Y, Mizoguchi M, Hata N, et al. Detection of proneural/mesenchymal marker expression in glioblastoma: temporospatial dynamics and association with chromatin-modifying gene expression. J Neuro-Oncol. 2015;125:33–41.CrossRefGoogle Scholar
  63. Nagarajan RP, Costello JF. Epigenetic mechanisms in glioblastoma multiforme. Semin Cancer Biol. 2009;19:188–97.CrossRefGoogle Scholar
  64. Nakano I. Stem cell signature in glioblastoma: therapeutic development for a moving target. J Neurosurg. 2015;122:324–30.CrossRefGoogle Scholar
  65. Nakashima K. Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science. 1999;284:479–82.CrossRefGoogle Scholar
  66. Namihira M, Nakashima K. Mechanisms of astrocytogenesis in the mammalian brain. Curr Opin Neurobiol. 2013;23:921–7.CrossRefGoogle Scholar
  67. Namihira M, Kohyama J, Semi K, Sanosaka T, Deneen B, Taga T, et al. Committed neuronal precursors confer astrocytic potential on residual neural precursor cells. Dev Cell. 2009;16:245–55.CrossRefGoogle Scholar
  68. Natsume A, Kondo Y, Ito M, Motomura K, Wakabayashi T, Yoshida J. Epigenetic aberrations and therapeutic implications in gliomas. Cancer Sci. 2010;101:1331–6.CrossRefGoogle Scholar
  69. Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP, et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010;17:510–22.CrossRefGoogle Scholar
  70. Ohnishi K, Semi K, Yamamoto T, Shimizu M, Tanaka A, Mitsunaga K, et al. Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation. Cell. 2014;156:663–77.CrossRefGoogle Scholar
  71. Park NI, Guilhamon P, Desai K, Mcadam RF, Langille E, O'connor M, et al. ASCL1 reorganizes chromatin to direct neuronal fate and suppress tumorigenicity of glioblastoma stem cells. Cell Stem Cell. 2017;21(2):209–224.e7.CrossRefGoogle Scholar
  72. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321:1807–12.CrossRefGoogle Scholar
  73. Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, et al. Single-cell Rna-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014;344:1396–401.CrossRefGoogle Scholar
  74. Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006;9:157–73.CrossRefGoogle Scholar
  75. Qian X, Shen Q, Goderie SK, He W, Capela A, Davis AA, et al. Timing of CNS cell generation: a programmed sequence of neuron and glial cell production from isolated murine cortical stem cells. Neuron. 2000;28:69–80.CrossRefGoogle Scholar
  76. Qureshi IA, Mehler MF. Understanding neurological disease mechanisms in the era of epigenetics. JAMA Neurol. 2013;70:703–10.CrossRefGoogle Scholar
  77. Sato R, Semba T, Saya H, Arima Y. Concise review: stem cells and epithelial-mesenchymal transition in cancer: biological implications and therapeutic targets. Stem Cells. 2016;34:1997–2007.CrossRefGoogle Scholar
  78. Shen S, Li J, Casaccia-Bonnefil P. Histone modifications affect timing of oligodendrocyte progenitor differentiation in the developing rat brain. J Cell Biol. 2005;169:577–89.CrossRefGoogle Scholar
  79. Sherry-Lynes MM, Sengupta S, Kulkarni S, Cochran BH. Regulation of the JMJD3 (KDM6B) histone demethylase in glioblastoma stem cells by STAT3. PLoS One. 2017;12:e0174775.CrossRefGoogle Scholar
  80. Silber J, Lim DA, Petritsch C, Persson AI, Maunakea AK, Yu M, et al. miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. Bmc Med. 2008;6:14.CrossRefGoogle Scholar
  81. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, et al. Identification of human brain tumour initiating cells. Nature. 2004;432:396–401.CrossRefGoogle Scholar
  82. Singh MM, Johnson B, Venkatarayan A, Flores ER, Zhang J, Su X, et al. Preclinical activity of combined HDAC and KDM1A inhibition in glioblastoma. Neuro-Oncology. 2015;17:1463–73.CrossRefGoogle Scholar
  83. Sloan SA, Barres BA. Mechanisms of astrocyte development and their contributions to neurodevelopmental disorders. Curr Opin Neurobiol. 2014;27:75–81.CrossRefGoogle Scholar
  84. Song MR, Ghosh A. FGF2-induced chromatin remodeling regulates CNTF-mediated gene expression and astrocyte differentiation. Nat Neurosci. 2004;7:229–35.CrossRefGoogle Scholar
  85. Stupp R, Mason WP, Van Den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96.CrossRefGoogle Scholar
  86. Suva ML, Rheinbay E, Gillespie SM, Patel AP, Wakimoto H, Rabkin SD, et al. Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Cell. 2014;157:580–94.CrossRefGoogle Scholar
  87. Talbert PB, Henikoff S. Histone variants—ancient wrap artists of the epigenome. Nat Rev Mol Cell Biol. 2010;11:264–75.CrossRefGoogle Scholar
  88. Tsuyama J, Bunt J, Richards LJ, Iwanari H, Mochizuki Y, Hamakubo T, et al. MicroRNA-153 regulates the acquisition of gliogenic competence by neural stem cells. Stem Cell Rep. 2015;5:365–77.CrossRefGoogle Scholar
  89. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17:98–110.CrossRefGoogle Scholar
  90. Visvanathan J, Lee S, Lee B, Lee JW, Lee SK. The microRNA miR-124 antagonizes the anti-neural REST/SCP1 pathway during embryonic CNS development. Genes Dev. 2007;21:744–9.CrossRefGoogle Scholar
  91. Westphal M, Lamszus K. Circulating biomarkers for gliomas. Nat Rev Neurol. 2015;11:556–66.CrossRefGoogle Scholar
  92. Williams MJ, Singleton WG, Lowis SP, Malik K, Kurian KM. Therapeutic targeting of histone modifications in adult and pediatric high-grade glioma. Front Oncol. 2017;7:45.CrossRefGoogle Scholar
  93. Yamada Y, Haga H, Yamada Y. Concise review: dedifferentiation meets cancer development: proof of concept for epigenetic cancer. Stem Cells Transl Med. 2014;3:1182–7.CrossRefGoogle Scholar
  94. Yao B, Christian KM, He C, Jin P, Ming GL, Song H. Epigenetic mechanisms in neurogenesis. Nat Rev Neurosci. 2016;17(9):537–49.CrossRefGoogle Scholar
  95. Ye F, Chen Y, Hoang T, Montgomery RL, Zhao XH, Bu H, et al. HDAC1 and HDAC2 regulate oligodendrocyte differentiation by disrupting the beta-catenin-TCF interaction. Nat Neurosci. 2009;12:829–38.CrossRefGoogle Scholar
  96. Yoon K, Gaiano N. Notch signaling in the mammalian central nervous system: insights from mouse mutants. Nat Neurosci. 2005;8:709–15.CrossRefGoogle Scholar
  97. Zhang W, Zhang J, Hoadley K, Kushwaha D, Ramakrishnan V, Li S, et al. miR-181d: a predictive glioblastoma biomarker that downregulates MGMT expression. Neuro-Oncology. 2012;14:712–9.CrossRefGoogle Scholar
  98. Zhang K, Sun X, Zhou X, Han L, Chen L, Shi Z, et al. Long non-coding RNA HOTAIR promotes glioblastoma cell cycle progression in an EZH2 dependent manner. Oncotarget. 2015;6:537–46.Google Scholar
  99. Zhou Q, Anderson DJ. The bHLH transcription factors OLIG2 and OLIG1 couple neuronal and glial subtype specification. Cell. 2002;109:61–73.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  • Yoichiro Kawamura
    • 1
    • 2
  • Jun Takouda
    • 1
  • Koji Yoshimoto
    • 2
  • Kinichi Nakashima
    • 1
    Email author
  1. 1.Division of Basic Stem Cell Biology, Department of Stem Cell Biology and Medicine, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
  2. 2.Department of Neurosurgery, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan

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