An update on the epigenetics of glioblastomas

Epigenomics

Volumn 8, Issue 9, 2016, Pages 1289-1305

  Ferreira, Wallax Augusto Silva ^a   Pinheiro, Danilo Do Rosário ^a   Costa Junior, Carlos Antonio Da ^a   Rodrigues Antunes, Symara ^a   Araújo, Mariana Diniz ^a   Leão Barros, Mariceli Baia ^a   Teixeira, Adriana Corrêa De Souza ^a   Faro, Thamirys Aline Silva ^a   Burbano, Rommel Rodriguez ^b   Oliveira, Edivaldo Herculano Correa De ^c   Harada, Maria Lúcia ^a   Borges, Bárbara Do Nascimento ^a  

^a FEDERAL UNIVERSITY OF PARÁ   (Brazil)

^b UFPA   (Brazil)

^c INSTITUTO EVANDRO CHAGAS   (Brazil)

Author keywords

astrocytomas; biomarkers; brain tumors; cancer; DNA methylation; epigenetic regulation; genetic; glioblastoma; gliomas; targeted therapy

Indexed keywords

DNA; HISTONE; HISTONE DEACETYLASE INHIBITOR; LONG UNTRANSLATED RNA; MICRORNA; UNTRANSLATED RNA; TUMOR MARKER;

CANCER GENETICS; CANCER STEM CELL; CARCINOGENESIS; DNA METHYLATION; EPIGENETICS; GENE EXPRESSION; GLIOBLASTOMA; HISTONE ACETYLATION; HISTONE METHYLATION; HISTONE MODIFICATION; HUMAN; MOLECULAR PATHOLOGY; MOLECULARLY TARGETED THERAPY; NEUROPATHOLOGY; PRIORITY JOURNAL; REVIEW; BRAIN TUMOR; GENE EXPRESSION REGULATION; GENETIC EPIGENESIS; GENETICS; METABOLISM; PATHOLOGY;

BIOMARKERS, TUMOR; BRAIN NEOPLASMS; EPIGENESIS, GENETIC; GENE EXPRESSION REGULATION, NEOPLASTIC; GLIOBLASTOMA; HUMANS;

EID: 84986903161     PISSN: 17501911     EISSN: 1750192X     Source Type: Journal    
DOI: 10.2217/epi-2016-0040     Document Type: Review

References (224)

1. Adamson C, Kanu OO, Mehta AI et al. Glioblastoma multiforme: a review of where we have been and where we are going. Expert Opin. Investig. Drugs 18, 1061-1083 (2009).
2. Wang LJ, Bai Y, Bao ZS et al. Hypermethylation of testis derived transcript gene promoter significantly correlates with worse outcomes in glioblastoma patients. Chin. Med. J. (Engl.) 126, 2062-2066 (2013).
3. Inda M-D-M, Bonavia R, Seoane J. Glioblastoma multiforme: a look inside its heterogeneous nature. Cancers 6, 226-239 (2014).
4. Sturm D, Bender S, Jones DTW et al. Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge. Nat. Rev. Cancer 14, 92-107 (2014).
5. Carén H, Pollard SM, Beck S. The good, the bad and the ugly: epigenetic mechanisms in glioblastoma. Mol. Aspects. Med. 34, 849-862 (2013).
6. Brennan CW, Verhaak RG, McKenna A et al. The somatic genomic landscape of glioblastoma. Cell 155, 462-477 (2013).
7. Ichimura K, Pearson DM, Kocialkowski S et al. IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. Neuro Oncol. 11, 341-347 (2009).
8. Yan H, Parsons DW, Jin G et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 2248-2249 (2009).
9. Waitkus MS, Diplas BH, Yan H. Isocitrate dehydrogenase mutations in gliomas. Neuro Oncol. 18, 16-26 (2016).
10. Bastien JIL, Mcneill KA, Fine HA. Molecular characterizations of glioblastoma, targeted therapy, and clinical results to date. Cancer 121, 502-516 (2015).
11. Rankeillor KL, Cairns DA, Loughrey C et al. Methylationspecific multiplex ligation-dependent probe amplification identifies promoter methylation events associated with survival in glioblastoma. J. Neurooncol. 117, 243-251 (2014).
12. Wen PY, Kesari S. Malignant gliomas in adults. N. Engl. J. Med. 359, 492-507 (2008).
13. Phillips HS, Kharbanda S, Chen R et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9, 157-173 (2006).
14. Li A, Walling J, Ahn S et al. Unsupervised analysis of transcriptomic profiles reveals six glioma subtypes. Cancer Res. 69, 2091-2099 (2009).
15. Verhaak RG, Hoadley KA, Purdom E et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17, 98-110 (2010).
16. Noushmehr H, Weisenberger DJ, Diefes K et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17, 510-522 (2010).
17. Kloosterhof NK, Rooi JJD, Kros M et al. Molecular subtypes of glioma identified by genome-wide methylation profiling. Genes Chromosomes Cancer 52, 665-674 (2013).
18. Kim T-M, Huang W, Park R et al. A developmental taxonomy of glioblastoma defined and maintained by microRNAs. Cancer Res. 71, 3387-3399 (2011).
19. Brennan C, Momota H, Hambardzumyan D et al. Glioblastoma subclasses can be defined by activity among signal transduction pathways and associated genomic alterations. PLoS ONE 4, e7752 (2009).
20. Maleszewska M, Kaminska B. Is glioblastoma an epigenetic malignancy? Cancers 5, 1120-1139 (2013).
21. Jones PA, Baylin SB. The epigenomics of cancer. Cell 128, 683-692 (2007).
22. Mariño-Ramírez L, Kann MG, Shoemaker BA, Landsman D. Histone structure and nucleosome stability. Expert Rev. Proteomics 2, 719-729 (2005).
23. Kim YZ. Altered histone modifications in gliomas. Brain Tumor Res. Treat. 2, 7-21 (2014).
24. Moreno NN, Giono LE, Botto AEC et al. Chromatin, DNA structure and alternative splicing. FEBS Letters 589, 3370-3378 (2015).
25. Galvani A, Thiriet C. Nucleosome dancing at the tempo of histone tail acetylation. Genes 6, 607-621 (2015).
26. Jenuwein T, Allis CD. Translating the histone code. Science 293, 1074-1080 (2001).
27. Parbin S, Kar S, Shilpi A et al. Histone deacetylases: a saga of perturbed acetylation homeostasis in cancer. J. Histochem. Cytochem. 62, 11-33 (2014).
28. Zentner GE, Henikoff S. Regulation of nucleosome dynamics by histone modifications. Nat. Struct. Mol. Biol. 20, 259-266 (2013).
29. Wang Z, Zang C, Cui K et al. Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell 138, 1019-1031 (2009).
30. Kruhlak MJ, Hendzel MJ, Fischle W et al. Regulation of global acetylation in mitosis through loss of histone acetyltransferases and deacetylases from chromatin. J. Biol. Chem. 276, 38307-38319 (2001).
31. Montezuma D, Henrique RMF, Jeronimo C. Altered expression of histone deacetylases in cancer. Crit. Rev. Oncog. 20, 19-34 (2015).
32. Ropero S, Esteller M. The role of histone deacetylases (HDACs) in human cancer. Mol. Oncol. 1, 19-25 (2007).
33. Barneda-Zahonero B, Parra M. Histone deacetylases and cancer. Mol. Oncol. 6, 579-589 (2012).
34. Tang J, Yan H, Zhuang S. Histone deacetylases as targets for treatment of multiple diseases. Clin. Sci. 124, 651-662 (2013).
35. Mohseni J, Zabidi-Hussin Z, Sasongko TH. Histone deacetylase inhibitors as potential treatment for spinal muscular atrophy. Genet. Mol. Biol. 36, 299-307 (2013).
36. Perry J, Okamoto M, Guiou M, Shirai K, Errett A, Chakravarti A. Novel therapies in glioblastoma. Neurol. Res. Int. 2012 1-14 (2012).
37. Friday BB, Anderson SK, Buckner J et al. Phase II trial of vorinostat in combination with bortezomib in recurrent glioblastoma: a North Central Cancer Treatment Group study. Neuro Oncol. 14, 215-221 (2012).
38. Xu J, Sampath D, Lang FF et al. Vorinostat modulates cell cycle regulatory proteins in glioma cells and human glioma slice cultures. J. Neurooncol. 105, 241-251 (2011).
39. Orzan F, Pellegatta S, Poliani PL et al. Enhancer of zeste 2 (EZH2) is up-regulated in malignant gliomas and in glioma stem-like cells. Neuropathol. Appl. Neurobiol. 37, 381-394 (2011).
40. Xiao Y. Enhancer of zeste homolog 2: a potential target for tumor therapy. Int. J. Biochem. Cell. Biol. 43, 474-477 (2011).
41. Singh MM, Johnson B, Venkatarayan A et al. Preclinical activity of combined HDAC and KDM1A inhibition in glioblastoma. Neuro Oncol. 17, 1463-1473 (2015).
42. Lee EQ, Puduvalli VK, Reid JM et al. Phase I study of vorinostat in combination with temozolomide in patients with high-grade gliomas: North American Brain Tumor Consortium Study 04-03. Clin. Cancer Res. 18, 6032-6039 (2012).
43. Galanis E, Jaeckle KA, Maurer MJ et al. Phase II trial of vorinostat in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group study. J. Clin. Oncol. 27, 2052-2058 (2009).
44. Pont LMB, Kleijn A, Kloezeman JJ et al. The HDAC inhibitors scriptaid and LBH589 combined with the oncolytic virus Delta24-RGD exert enhanced anti-tumor efficacy in patient-derived glioblastoma cells. PLoS ONE 10, e0127058 (2015).
45. Dokmanovic M, Clarke C, Marks PA. Histone deacetylase inhibitors: overview and perspectives. Mol. Cancer Res. 5, 981-989 (2007).
46. Alvarez AA, Field M, Bushnev S et al. The effects of histone deacetylase inhibitors on glioblastoma-derived stem cells. J. Mol. Neurosci. 55, 7-20 (2015).
47. Ekström T, Almqvist P, Svechnikova I. HDAC inhibitors effectively induce cell type-specific differentiation in human glioblastoma cell lines of different origin. Int. J. Oncol. 32, 821-827 (2008).
48. Höring E, Podlech O, Silkenstedt B et al. The histone deacetylase inhibitor trichostatin a promotes apoptosis and antitumor immunity in glioblastoma cells. Anticancer Res. 33, 1351-1360 (2013).
49. Eisele G, Wischhusen J, Mittelbronn M et al. TGF-beta and metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells. Brain 129, 2416-2425 (2006).
50. Armeanu S, Bitzer M, Lauer UM et al. Natural killer cellmediated lysis of hepatoma cells via specific induction of NKG2D ligands by the histone deacetylase inhibitor sodium valproate. Cancer Res. 65, 6321-6329 (2005).
51. Adamopoulou E, Naumann U. HDAC inhibitors and their potential applications to glioblastoma therapy. Oncoimmunology 2, e25219 (2013).
52. Kusaczuk M, Krκtowski R, Bartoszewicz M et al. Phenylbutyrate - a pan-HDAC inhibitor - suppresses proliferation of glioblastoma LN-229 cell line. Tumour Biol. 1-12 (2015).
53. Hazane-Puch F, Arnaud J, Trocmé C et al. Sodium selenite decreased HDAC activity, cell proliferation and induced apoptosis in three human glioblastoma cells. Anticancer Agents Med. Chem. 16, 490-500 (2016).
54. Gryder BE, Sodji QH, Oyelere AK. Targeted cancer therapy: giving histone deacetylase inhibitors all they need to succeed. Future Med. Chem. 4, 505-524 (2012).
55. Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 21, 381-395 (2011).
56. Cheung P, Lau P. Epigenetic regulation by histone methylation and histone variants. Mol. Endocrinol. 19, 563-573 (2005).
57. Kooistra SM, Helin K. Molecular mechanisms and potential functions of histone demethylases. Nat. Rev. Mol. Cell Biol. 13, 297-311 (2012).
58. Creyghton MP, Cheng AW, Welstead GG et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc. Natl Acad. Sci. USA 107, 21931-21936 (2010).
59. Liang G, Lin JC, Wei V et al. Distinct localization of histone H3 acetylation and H3-K4 methylation to the transcription start sites in the human genome. Proc. Natl Acad. Sci. USA 101, 7357-7362 (2004).
60. Parsons DW, Jones S, Zhang X et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807-1812 (2008).
61. Black JC, Van Rechem C, Whetstine JR. Histone lysine methylation dynamics: establishment, regulation, and biological impact. Mol. Cell 48, 491-507 (2012).
62. Chan KM, Fang D, Gan H et al. The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes Dev. 27, 985-990 (2013).
63. Sturm D, Witt H, Hovestadt V et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22, 425-437 (2012).
64. Bender S, Tang Y, Lindroth AM et al. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell 24, 660-672 (2013).
65. Lewis PW, Müller MM, Koletsky MS et al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 340, 857-861 (2013).
66. Nagarajan RP, Zhang B, Bell RJ et al. Recurrent epimutations activate gene body promoters in primary glioblastoma. Genome Res. 24, 761-774 (2014).
67. Ott M, Litzenburger UM, Sahm F et al. Promotion of glioblastoma cell motility by enhancer of zeste homolog 2 (EZH2) is mediated by AXL receptor kinase. PLoS ONE 7, e47663 (2012).
68. Natsume A, Ito M, Katsushima K et al. Chromatin regulator PRC2 is a key regulator of epigenetic plasticity in glioblastoma. Cancer Res. 73, 4559-4570 (2013).
69. Baldwin RM, Morettin A, Côté J. Role of PRMTs in cancer: could minor isoforms be leaving a mark? World J. Biol. Chem. 5, 115-129 (2014).
70. Yan F, Alinari L, Lustberg ME et al. Genetic validation of the protein arginine methyltransferase PRMT5 as a candidate therapeutic target in glioblastoma. Cancer Res. 74, 1752-1765 (2014).
71. 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).
72. Mongiardi MP, Savino M, Bartoli L et al. MYC and OMOMYC functionally associate with the protein arginine methyltransferase 5 (PRMT5) in glioblastoma cells. Sci. Rep. 5, 15494 (2015).
73. Banelli B, Carra E, Barbieri F et al. The histone demethylase KDM5A is a key factor for the resistance to temozolomide in glioblastoma. Cell Cycle 14, 3418-3429 (2015).
74. Cloos PA, Christensen J, Agger K et al. Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease. Genes Dev. 22, 1115-1140 (2008).
75. Ene CI, Edwards L, Riddick G et al. Histone demethylase Jumonji D3 (JMJD3) as a tumor suppressor by regulating p53 protein nuclear stabilization. PLoS ONE 7, e51407 (2012).
76. Perrigue PM, Silva ME, Warden CD et al. The histone demethylase Jumonji coordinates cellular senescence including secretion of neural stem cell-attracting cytokines. Mol. Cancer Res. 13, 636-650 (2015).
77. Liu BL, Cheng JX, Zhang X et al. Global histone modification patterns as prognostic markers to classify glioma patients. Cancer Epidemiol. Biomarkers Prev. 19, 2888-2896 (2010).
78. Kozono D, Li J, Nitta M et al. Dynamic epigenetic regulation of glioblastoma tumorigenicity through LSD1 modulation of MYC expression. Proc. Natl. Acad. Sci. USA 112, E4055-E4064 (2015).
79. Costa BM, Smith JS, Chen Y et al. Reversing HOXA9 oncogene activation by PI3K inhibition: epigenetic mechanism and prognostic significance in human glioblastoma. Cancer Res. 70, 453-462 (2010).
80. Alaminos M, Dávalos V, Ropero S et al. Emp3, a myelinrelated gene located in the critical 19q13.3 region, is epigenetically silenced and exhibits features of a candidate tumor suppressor in glioma and neuroblastoma. Cancer Res. 65, 2565-2571 (2005).
81. Hesson L, Bièche I, Krex D et al. Frequent epigenetic inactivation of RASSF1A and BLU genes located within the critical 3p21.3 region in gliomas. Oncogene 23, 2408-2419 (2004).
82. Malzkorn B, Wolter M, Riemenschneider MJ et al. Unraveling the glioma epigenome: from molecular mechanisms to novel biomarkers and therapeutic targets. Brain Pathol. 21, 619-632 (2011).
83. Hyman G, Manglik V, Rousch JM et al. Epigenetic approaches in glioblastoma multiforme and their implication in screening and diagnosis. Methos. Mol. Biol. 1238, 511-521 (2015).
84. Dunn GP, Rinne ML, Wykosky J et al. Emerging insights into the molecular and cellular basis of glioblastoma. Genes Dev. 26, 756-784 (2012).
85. Stratton MR, Campbell P, Futreal P. The cancer genome. Nature 458, 719-724 (2009).
86. Esteller M. CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene 21, 5427-5440 (2002).
87. Wolf SF, Jolly DJ, Lunnen KD et al. Methylation of the hypoxanthine phosphoribosyltransferase locus on the human X chromosome: implications for X-chromosome inactivation. Proc. Natl Acad. Sci. USA 81(9), 2806-2810 (1984).
88. Agnihotri S, Wolf A, Munoz DM et al. A GATA4-regulated tumor suppressor network represses formation of malignant human astrocytomas. J. Exp. Med. 208, 689-702 (2011).
89. Tepel M, Roerig P, Wolter M et al. Frequent promoter hypermethylation and transcriptional downregulation of the NDRG2 gene at 14q11.2 in primary glioblastoma. Int. J. Cancer 123(9), 2080-2086 (2008).
90. Nakamura M, Watanabe T, Yonekawa Y et al. Promoter methylation of the DNA repair gene MGMT in astrocytomas is frequently associated with G:C -> A:T mutations of the TP53 tumor suppressor gene. Carcinogenesis 22, 1715-1719 (2001).
91. Eoli M, Menghi F, Bruzzone MG et al. Methylation of O6-methylguanine DNA methyltransferase and loss of heterozygosity on 19q and/or 17p are overlapping features of secondary glioblastomas with prolonged survival. Clin. Cancer Res. 13, 2606-2613 (2007).
92. Stone AR, Bobo W, Brat DJ et al. Aberrant methylation and down-regulation of TMS1/ASC in human glioblastoma. Am. J. Pathol. 165, 1151-1161 (2004).
93. Kosla K, Pluciennik E, Kurzyk A et al. Molecular analysis of WWOX expression correlation with proliferation and apoptosis in glioblastoma multiforme. J. Neurooncol. 101, 207-213 (2011).
94. Waha A, Güntner S, Huang TH et al. Epigenetic silencing of the protocadherin family member PCDH-gamma-A11 in astrocytomas. Neoplasia 7, 193-199 (2005).
95. Lindemann C, Hackmann O, Delic S et al. SOCS3 promoter methylation is mutually exclusive to EGFR amplification in gliomas and promotes glioma cell invasion through STAT3 and FAK activation. Acta Neuropathol. 122, 241-251 (2011).
96. Alonso MM, Diez-Valle R, Manterola L et al. Genetic and epigenetic modifications of Sox2 contribute to the invasive phenotype of malignant gliomas. PLoS ONE 6, e26740 (2011).
97. Dubuc AM, Mack S, Unterberger A et al. The epigenetics of brain tumors. Methods in molecular biology cancer epigenetics. Methods Mol. Biol. 863, 139-153 (2012).
98. Foltz G, Ryu GY, Yoon JG et al. Genome-wide analysis of epigenetic silencing identifies BEX1 and BEX2 as candidate tumor suppressor genes in malignant glioma. Cancer Res. 66, 6665-6674 (2006).
99. Laffaire J, Everhard S, Idbaih A et al. Methylation profiling identifies 2 groups of gliomas according to their tumorigenesis. Neuro Oncol. 13, 84-98 (2011).
100. Martinez R, Martin-Subero JI, Rohde V et al. A microarraybased DNA methylation study of glioblastoma multiforme. Epigenetics 4, 255-264 (2009).
101. Mueller W, Nutt CL, Ehrich M et al. Downregulation of RUNX3 and TES by hypermethylation in glioblastoma. Oncogene 26, 583-593 (2007).
102. Schmidt N, Windmann S, Reifenberger G et al. DNA hypermethylation and histone modifications downregulate the candidate tumor suppressor gene RRP22 on 22q12 in human gliomas. Brain Pathol. 22, 17-25 (2012).
103. Bozdag S, Li A, Riddick G et al. Age-specific signatures of glioblastoma at the genomic, genetic, and epigenetic levels. PLoS ONE 8, e62982 (2013).
104. Etcheverry A, Aubry M, Tayrac MD et al. DNA methylation in glioblastoma: impact on gene expression and clinical outcome. BMC Genomics 11, 701 (2010).
105. McNamara MG, Sahebjam S, Mason WP. Emerging biomarkers in glioblastoma. Cancers (Basel) 5, 1103-1119 (2013).
106. Pegg AE. Repair of O(6)-alkylguanine by alkyltransferases. Mutat. Res. 462, 83-100 (2000).
107. Stupp R, Hegi ME, Mason WP et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised Phase III study: 5 year analysis of the EORTCNCIC trial. Lancet Oncol. 10, 459-466 (2009).
108. Weller M, Felsberg J, Hartmann C et al. Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network. J. Clin. Oncol. 27, 5743-5750 (2009).
109. Riemenschneider MJ, Hegi ME, Reifenberger G. MGMT promoter methylation inmalignant gliomas. Target Oncol. 5, 161-165 (2010).
110. Ang C, Guiot MC, Ramanakumar AV et al. Clinical significance of molecular biomarkers in glioblastoma. Can. J. Neurol. Sci. 37: 625-630 (2010).
111. Blanc JL, Wager M, Guilhot J et al. Correlation of clinical features and methylation status of MGMT gene promoter in glioblastomas. J. Neurooncol. 68, 275-283 (2004).
112. Bleeker FE, Molenaar RJ, Leenstra S. Recent advances in the molecular understanding of glioblastoma. J. Neurooncol. 108, 11-27 (2012).
113. Zawlik I, Vaccarella S, Kita D et al. Promoter methylation and polymorphisms of the MGMT gene in glioblastomas: a population-based study. Neuroepidemiology 32, 21-29 (2009).
114. Brennan CW, Verhaak RGW, McKenna A et al. The somatic genomic landscape of glioblastoma. Cell 155, 462-477 (2013).
115. Buckner JC, Ballman KV, Michalak JC et al. Phase III trial of carmustine and cisplatin compared with carmustine alone and standard radiation therapy or accelerated radiation therapy in patients with glioblastoma multiforme: North Central Cancer Treatment Group 93-72-52 and Southwest Oncology Group 9503 Trials. J. Clin. Oncol. 24, 3871-2879 (2006).
116. Halperin EC, Herndon J, Schold SC et al. A Phase III randomized prospective trial of external beam radiotherapy, mitomycin C, carmustine, and 6-mercaptopurine for the treatment of adults with anaplastic glioma of the brain. CNS Cancer Consortium. Int. J. Radiat. Oncol. Biol. Phys. 34, 793-802 (1996).
117. Stewart LA. Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359, 1011-1018 (2002).
118. Shen L, Ahuja N, Shen Y et al. DNA methylation and environmental exposures in human hepatocellular carcinoma. J. Natl Cancer Inst. 94, 755-761 (2002).
119. Toyota M, Ahuja N, Ohe-Toyota M et al. CpG island methylator phenotype in colorectal cancer. Proc. Natl Acad. Sci. USA 96, 8681-8686 (1999).
120. Hinoue T, Weisenberger DJ, Lange CP et al. Genome-scale analysis of aberrant DNA methylation in colorectal cancer. Genome Res. 22, 271-282 (2012).
121. Issa JP. CpG island methylator phenotype in cancer. Nat. Rev. Cancer 4, 988-993 (2004).
122. Toyota M, Ahuja N, Suzuki H et al. Aberrant methylation in gastric cancer associated with the CpG island methylator phenotype. Cancer Res. 59, 5438-5442 (1999).
123. Suzuki M, Shigematsu H, Iizasa T et al. Exclusive mutation in epidermal growth factor receptor gene, HER-2, and KRAS, and synchronous methylation of nonsmall cell lung cancer. Cancer 106, 2200-2207 (2006).
124. Ueki T, Toyota M, Sohn T et al. Hypermethylation of multiple genes in pancreatic adenocarcinoma. Cancer Res. 60, 1835-1839 (2000).
125. Strathdee G, Appleton K, Illand M et al. Primary ovarian carcinomas display multiple methylator phenotypes involving known tumor suppressor genes. Am. J. Pathol. 158, 1121-1127 (2001).
126. Roman-Gomez J, Jimenez-Velasco A, Agirre X et al. Lack of CpG island methylator phenotype defines a clinical subtype of T-cell acute lymphoblastic leukemia associated with good prognosis. J. Clin. Oncol. 23, 7043-7049 (2005).
127. Turcan S, Rohle D, Goenka A et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479-483 (2012).
128. Mazor T, Pankov A, Johnson BE et al. DNA methylation and somatic mutations converge on the cell cycle and define similar evolutionary histories in brain tumors. Cancer Cell 28, 307-317 (2015).
129. Baysan M, Bozdag S, Cam MC et al. G-cimp status prediction of glioblastoma samples using mRNA expression data. PLoS ONE 7, e47839 (2012).
130. van den Bent MJ, Gravendeel LA, Gorlia T et al. A hypermethylated phenotype is a better predictor of survival than MGMT methylation in anaplastic oligodendroglial brain tumors: a report from EORTC study 26951. Clin. Cancer Res. 17, 7148-7155 (2011).
131. Cadieux B, Ching TT, VandenBerg SR et al. Genome-wide hypomethylation in human glioblastomas associated with specific copy number alteration, methylenetetrahydrofolate reductase allele status, and increased proliferation. Cancer Res. 66, 8469-8476 (2006).
132. Jackson K, Yu MC, Arakawa K et al. DNA hypomethylation is prevalent even in low-grade breast cancers. Cancer Biol. Ther. 3, 1225-1231 (2004).
133. Nagarajan RP, Costello JF. Epigenetic mechanisms in glioblastoma multiforme. Semin. Cancer Biol. 19, 188-197 (2009).
134. Lai RK, Chen Y, Guan X et al. Genome-wide methylation analyses in glioblastoma multiforme. PLoS ONE 9(2), e89376 (2014).
135. Alelú-Paz R, Ashour N, González-Corpas A et al. DNA methylation, histone modifications, and signal transduction pathways: a close relationship in malignant gliomas pathophysiology. J. Signal. Transduct. 2012 956958 (2012).
136. Soroceanu L, Kharbanda S, Chen R et al. Identification of IGF2 signaling through phosphoinositide-3-kinase regulatory subunit 3 as a growth-promoting axis in glioblastoma. Proc. Natl Acad. Sci. USA 104, 3466-3471 (2007).
137. Wang H, Wang Y, Bao Z et al. Hypomethylated Rab27b is a progression-associated prognostic biomarker of glioma regulating MMP-9 to promote invasion. Oncol. Rep. 34, 1503-1509 (2015).
138. Liu X, Tang H, Wang Z et al. F10 gene hypomethylation, a putative biomarker for glioma prognosis. J. Neurooncol. 107, 479-485 (2012).
139. Liu X, Tang H, Zhang Z et al. POTEH hypomethylation, a new epigenetic biomarker for glioma prognosis. Brain Res. 1391, 125-131 (2011).
140. Alonso MM, Diez-Valle R, Manterola L et al. Genetic and epigenetic modifications of Sox2 contribute to the invasive phenotype of malignant gliomas. PLoS ONE 6, e26740 (2011).
141. Shi J, Shi W, Ni L et al. OCT4 is epigenetically regulated by DNA hypomethylation of promoter and exon in primary gliomas. Oncol. Rep. 30, 201-206 (2013).
142. Xiaoping L, Zhibin Y, Wenjuan L et al. CPEB1, a histonemodified hypomethylated gene, is regulated by miR-101 and involved in cell senescence in glioma. Cell Death Dis. 4, e675 (2013).
143. Kim VN. MicroRNA biogenesis: coordinated cropping and dicing. Nat. Rev. Mol. Cell. Biol. 6, 376-385 (2005).
144. Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15-20 (2005).
145. Green D, Dalmay T, Chapman T. Microguards and micromessengers of the genome. Heredity (Edinb.) 116(2), 125-134 (2015).
146. Dews M, Homayouni A, Yu D et al. Augmentation of tumor angiogenesis by a MYC-activated microRNA cluster. Nat. Genet. 38, 1060-1065 (2006).
147. Kumar MS, Lu J, Mercer KL et al. Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat. Genet. 39, 673-677 (2007).
148. Ohtsuka M, Ling H, Doki Y et al. MicroRNA processing and human cancer. J. Clin. Med. 4, 1651-1667 (2015).
149. Lu J, Getz G, Miska EA et al. MicroRNA expression profiles classify human cancers. Nature 435, 834-838 (2005).
150. Somasundaram K, Rao SAM, Nawaz Z. MicroRNA (miRNA) regulation in glioma: implications in development, progression, grading, prognosis and therapy. Molecular Targets of CNS Tumors. InTech, 686 (2011).
151. Areeb Z, Stylli SS, Koldej R, Ritchie DS et al. MicroRNA as potential biomarkers in glioblastoma. J. Neurooncol. 125, 237-248 (2015).
152. Ciafre SA, Galardi S, Mangiola A et al. Extensive modulation of a set of microRNAs in primary glioblastoma. Biochem. Biophys. Res. Commun. 334, 1351-1358 (2005).
153. Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 65, 6029-6033 (2005).
154. Silber J, Lim DA, Petritsch C et al. miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med. 6, 14(2008).
155. Lages E, Guttin A, El Atifi M et al. MicroRNA and target protein patterns reveal physiopathological features of glioma subtypes. PLoS ONE 6(5), e20600 (2011).
156. Godlewski J, Nowicki MO, Bronisz A et al. Targeting of the Bmi-1 oncogene/stem cell renewal factor by microRNA-128 inhibits glioma proliferation and self-renewal. Cancer Res. 68, 9125-9130 (2008).
157. Sasayama T, Nishihara M, Kondoh T et al. MicroRNA-10b is overexpressed in malignant glioma and associated with tumor invasive factors, uPAR and RhoC. Int. J. Cancer 125, 1407-1413 (2009).
158. Hua D, Mo F, Ding D et al. A catalogue of glioblastoma and brain microRNAs identified by deep sequencing. OMICS 16, 690-699 (2012).
159. Skalsky RL, Cullen BR. Reduced expression of brainenriched microRNAs in glioblastomas permits targeted regulation of a cell death gene. PLoS ONE 6, e24248 (2011).
160. Zhi F, Chen X, Wang S et al. The use of hsa-miR-21, hsamiR-181b and hsa-miR-106a as prognostic indicators of astrocytoma. Eur. J. Cancer 46, 1640-1649 (2010).
161. Qiu S, Lin S, Hu D et al. Interactions of miR-323/miR-326/ miR-329 and miR-130a/miR-155/miR-210 as prognostic indicators for clinical outcome of glioblastoma patients. J. Transl. Med. 11:10 (2013).
162. Zadran S, Remacle F, Levine R. Surprisal analysis of glioblastoma multiform (GBM) microRNA dynamics unveils tumor specific phenotype. PLoS ONE 9(9), e108171(2014).
163. Piwecka M, Rolle K, Wyszko E et al. Nucleic acid-based technologies in therapy of malignant gliomas. Curr. Pharm. Biotechnol. 12, 1805-1822 (2011).
164. Rolle K. miRNA multiplayers in glioma. From bench to bedside. Acta Biochim. Pol. 62, 353-365 (2015).
165. Srinivasan S, Patric IR, Somasundaram K. A ten-microRNA expression signature predicts survival in glioblastoma. PLoS ONE 6, e17438 (2011).
166. Zhang W, Zhang J, Yan W et al. Whole-genome microRNA expression profiling identifies a 5-microRNA signature as a prognostic biomarker in Chinese patients with primary glioblastoma multiforme. Cancer 119, 814-824 (2013).
167. Garzon R, Marcucci G, Croce CM. Targeting microRNAs in cancer: rationale, strategies and challenges. Nat. Rev. Drug Discov. 9, 775-789 (2010).
168. Gomes-da-Silva LC, Fernández Y, Abasolo I et al. Efficient intracellular delivery of siRNA with a safe multitargeted lipid-based nanoplatform. Nanomedicine (Lond.) 8, 1397-1413 (2013).
169. Mizoguchi M, Guan Y, Yoshimoto K et al. Clinical implications of microRNAs in human glioblastoma. Front. Oncol. 3, 19 (2013).
170. Mocellin S, Pasquali S, Pilati P. Oncomirs: from tumor biology to molecularly targeted anticancer strategies. Mini Rev. Med. Chem. 9, 70-80 (2009).
171. Anesti AM, Simpson GR, Price T et al. Expression of RNA interference triggers from an oncolytic herpes simplex virus results in specific silencing in tumour cells in vitro and tumours in vivo. BMC Cancer 10, 486 (2010).
172. Santos AO, da Silva LC, Bimbo LM et al. Design of peptidetargeted liposomes containing nucleic acids. Biochim. Biophys. Acta 1798, 433-441 (2010).
173. Ohno S, Takanashi M, Sudo K et al. Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol. Ther. 21, 185-191 (2013).
174. Yan Y, Zhang L, Jiang Y et al. LncRNA and mRNA interaction study based on transcriptome profiles reveals potential core genes in the pathogenesis of human glioblastoma multiforme. J. Cancer Res. Clin. Oncol. 141, 827-838 (2014).
175. Prensner JR, Chinnaiyan AM. The emergence of lncRNAs in cancer biology. Cancer Discov. 1, 391-407 (2011).
176. Han L, Zhang K, Shi Z et al. LncRNA profile of glioblastoma reveals the potential role of lncRNAs in contributing to glioblastoma pathogenesis. Int. J. Oncol. 40, 2004-2012 (2012).
177. Cao Y, Wang P, Ning S et al. Identification of prognostic biomarkers in glioblastoma using a long non-coding RNA-mediated, competitive endogenous RNA network. Oncotarget doi:10.18632/oncotarget.9569 (2016) (Epub ahead of print).
178. Li Y, Wang Z, Wang Y et al. Identification and characterization of lncRNA mediated transcriptional dysregulation dictates lncRNA roles in glioblastoma. Oncotarget doi:10.18632/oncotarget.7801 (2016) (Epub ahead of print).
179. Zhang K, Sun X, Zhou X et al. Long non-coding RNA HOTAIR promotes glioblastoma cell cycle progression in an EZH2 dependent manner. Oncotarget 1, 537-546 (2014).
180. Vassallo I, Zinn P, Lai M et al. WIF1 re-expression in glioblastoma inhibits migration through attenuation of noncanonical WNT signaling by downregulating the lncRNA MALAT1. Oncogene 35, 12-21 (2015).
181. Yao Y, Ma J, Xue Y et al. Knockdown of long non-coding RNA XIST exerts tumor-suppressive functions in human glioblastoma stem cells by up-regulating miR-152. Cancer Lett. 359, 75-86 (2015).
182. Lathia JD, Mack SC, Mulkearns-Hubert EE et al. Cancer stem cells in glioblastoma. Genes Dev. 29, 1203-1217 (2015).
183. Bradshaw A, Wickremsekera A, Tan ST et al. Cancer stem cell hierarchy in glioblastoma multiforme. Front. Surg. 3, 21 (2016).
184. Ignatova TN, Kukekov VG, Laywell ED et al. Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 39, 193-206 (2002).
185. Singh SK, Clarke ID, Terasaki M et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 63, 5821-5828 (2003).
186. Yuan X, Curtin J, Xiong Y et al. Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene 23, 9392-9400 (2004).
187. Beier D, Hau P, Proescholdt M et al. CD133 and CD133- glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res. 67, 4010-4015 (2007).
188. Kelly JJP, Stechishin O, Chojnacki A et al. Proliferation of human glioblastoma stem cells occurs independently of exogenous mitogens. Stem Cells 27, 1722-1733 (2009).
189. Piccirillo SG, Binda E, Fiocco R et al. Brain cancer stem cells. J. Mol. Med. (Berl.) 87, 1087-1095 (2009).
190. Field M, Alvarez A, Bushnev S et al. Embryonic stem cell markers distinguishing cancer stem cells from normal human neuronal stem cell populations in malignant glioma patients. Clin. Neurosurg. 57, 151-159 (2010).
191. Bhat KP, Balasubramaniyan V, Vaillant B et al. Mesenchymal differentiation mediated by NF-κb promotes radiation resistance in glioblastoma. Cancer Cell 24, 331-346 (2013).
192. Mao P, Joshi K, Li J et al. Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3. Proc. Natl Acad. Sci. USA 110, 8644-8649 (2013).
193. Codrici E, Enciu A-M, Popescu I-D et al. Glioma stem cells and their microenvironments: providers of challenging therapeutic targets. Stem Cells Int. 2016, 1-20 (2016).
194. Singh SK, Hawkins C, Clarke ID et al. Identification of human brain tumour initiating cells. Nature 432, 396-401 (2004).
195. Gangemi RMR, Griffero F, Marubbi D et al. SOX2 silencing in glioblastoma tumor-initiating cells causes stop of proliferation and loss of tumorigenicity. Stem Cells 27, 40-48 (2009).
196. Kalkan R. Glioblastoma stem cells as a new therapeutic target for glioblastoma. Clin. Med. Insights. Oncol. 9, 95-103 (2015).
197. Olmez I, Shen W, Mcdonald H et al. Dedifferentiation of patient-derived glioblastoma multiforme cell lines results in a cancer stem cell-like state with mitogen-independent growth. J. Cell. Mol. Med. 19, 1262-1272 (2015).
198. Zhang L, Yan Y, Jiang Y et al. The expression of SALL4 in patients with gliomas: high level of SALL4 expression is correlated with poor outcome. J. Neurooncol. 121, 261-268 (2015).
199. Rahaman SO, Harbor PC, Chernova O et al. Inhibition of constitutively active Stat3 suppresses proliferation and induces apoptosis in glioblastoma multiforme cells. Oncogene 21, 8404-8413 (2002).
200. Li L, Bhatia R. Stem cell quiescence. Clin. Cancer Res. 17, 4936-4941 (2011).
201. Reya T, Morrison SJ, Clarke MF et al. Stem cells, cancer, and cancer stem cells. Nature 414, 105-111 (2001).
202. Vescovi AL, Galli R, Reynolds BA. Brain tumour stem cells. Nat. Rev. Cancer 6, 425-436 (2006).
203. Bao S, Wu Q, McLendon RE et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756-760 (2006).
204. Rosen JM, Jordan CT. The increasing complexity of the cancer stem cell paradigm. Science 324, 1670-1673 (2009).
205. Park DM, Rich JN. Biology of glioma cancer stem cells. Mol. Cells 28, 7-12 (2009).
206. Heddleston JM, Li Z, Lathia JD et al. Hypoxia inducible factors in cancer stem cells. Br. J. Cancer 102, 789-795 (2010).
207. Frank NY, Schatton T, Frank MH. The therapeutic promise of the cancer stem cell concept. J. Clin. Invest. 120, 41-50 (2010).
208. Kanno H, Miyake S, Nakanowatari S. Signaling pathways in glioblastoma cancer stem cells: a role of Stat3 as a potential therapeutic target. Austin J. Cancer Clin. Res. 2, 1030 (2015).
209. Jahani-Asl A, Yin H, Soleimani VD et al. Control of glioblastoma tumorigenesis by feed-forward cytokine signaling. Nat. Neurosci. 19, 798-806 (2016).
210. Smith AW, Mehta MP, Wernicke AG. Neural stem cells, the subventricular zone and radiotherapy: implications for treating glioblastoma. J. Neurooncol. 128, 207-216 (2016).
211. Sanai N, Alvarez-Buylla A, Berger MS. Neural stem cells and the origin of gliomas. N. Engl. J. Med. 353, 811-822 (2005).
212. Barani IJ, Benedict SH, Lin P-S. Neural stem cells: implications for the conventional radiotherapy of central nervous system malignancies. Int. J. Radiat. Oncol. Biol. Phys. 68, 324-333 (2007).
213. Kut C, Redmond KJ. New considerations in radiation treatment planning for brain tumors: neural progenitor cell-containing niches. Semin. Radiat. Oncol. 24, 265-272 (2014).
214. Wang J, Wakeman TP, Lathia JD et al. Notch promotes radioresistance of glioma stem cells. Stem Cells 28, 17-28 (2010).
215. Liu G, Yuan X, Zeng Z et al. Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol. Cancer 5, 67 (2006).
216. Lepinoux-Chambaud C, Barreau K, Eyer J. The neurofilament-derived peptide NFL-TBS.40-63 targets neural stem cells and affects their properties. Stem Cells Transl. Med. 5(7), 901-913 (2016).
217. Seymour T, Nowak A, Kakulas F. Targeting aggressive cancer stem cells in glioblastoma. Front. Oncol. 5, 159 (2015).
218. Eramo A, Ricci-Vitiani L, Zeuner A et al. Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ. 13, 1238-1241 (2006).
219. Xu ZY, Wang K, Li XQ et al. The ABCG2 transporter is a key molecular determinant of the efficacy of sonodynamic therapy with Photofrin in glioma stem-like cells. Ultrasonics 53, 232-238 (2013).
220. Li WQ, Li YM, Tao BB et al. Downregulation of ABCG2 expression in glioblastoma cancer stem cells with miRNA-328 may decrease their chemoresistance. Med. Sci. Monit. 16, HY27-HY30 (2010).
221. Bleau A-M, Hambardzumyan D, Ozawa T et al. PTEN/ PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell 4, 226-235 (2009).
222. Yu Z, Zhao G, Xie G et al. Metformin and temozolomide act synergistically to inhibit growth of glioma cells and glioma stem cells in vitro and in vivo. Oncotarget 6, 32930-32943 (2015).
223. Shi L, Zhang S, Feng K et al. MicroRNA-125b-2 confers human glioblastoma stem cells resistance to temozolomide through the mitochondrial pathway of apoptosis. Int. J. Oncol. 40, 119-129 (2012).
224. Liebelt BD, Shingu T, Zhou X et al. Glioma stem cells: signalling, microenvironment, and therapy. Stem Cells Int. 2016, 7849890 (2016).