An Update on the Epigenetics of Glioblastomas

References

• Adamson C , KanuOO , MehtaAIet al. Glioblastoma multiforme: a review of where we have been and where we are going . Expert Opin. Investig. Drugs18 , 1061 – 1083 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Wang LJ , BaiY , BaoZSet al. Hypermethylation of testis derived transcript gene promoter significantly correlates with worse outcomes in glioblastoma patients . Chin. Med. J. (Engl.)126 , 2062 – 2066 ( 2013 ).
   PubMedGoogle Scholar
• Inda M-D-M , BonaviaR , SeoaneJ . Glioblastoma multiforme: a look inside its heterogeneous nature . Cancers6 , 226 – 239 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Sturm D , BenderS , JonesDTWet al. Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge . Nat. Rev. Cancer14 , 92 – 107 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Carén H , PollardSM , BeckS . The good, the bad and the ugly: epigenetic mechanisms in glioblastoma . Mol. Aspects. Med.34 , 849 – 862 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Brennan CW , VerhaakRG , McKennaAet al. The somatic genomic landscape of glioblastoma . Cell155 , 462 – 477 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Ichimura K , PearsonDM , KocialkowskiSet al. IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas . Neuro Oncol.11 , 341 – 347 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Yan H , ParsonsDW , JinGet al. IDH1 and IDH2 mutations in gliomas . N. Engl. J. Med.360 , 2248 – 2249 ( 2009 ).
   Google Scholar
• Waitkus MS , DiplasBH , YanH . Isocitrate dehydrogenase mutations in gliomas . Neuro Oncol.18 , 16 – 26 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Bastien JIL , McneillKA , FineHA . Molecular characterizations of glioblastoma, targeted therapy, and clinical results to date . Cancer121 , 502 – 516 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Rankeillor KL , CairnsDA , LoughreyCet al. Methylation-specific multiplex ligation-dependent probe amplification identifies promoter methylation events associated with survival in glioblastoma . J. Neurooncol.117 , 243 – 251 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Wen PY , KesariS . Malignant gliomas in adults . N. Engl. J. Med.359 , 492 – 507 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Phillips HS , KharbandaS , ChenRet al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis . Cancer Cell9 , 157 – 173 ( 2006 ).
   PubMed Web of Science ®Google Scholar
• Li A , WallingJ , AhnSet al. Unsupervised analysis of transcriptomic profiles reveals six glioma subtypes . Cancer Res.69 , 2091 – 2099 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Verhaak RG , HoadleyKA , PurdomEet al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1 . Cancer Cell17 , 98 – 110 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Noushmehr H , WeisenbergerDJ , DiefesKet al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma . Cancer Cell17 , 510 – 522 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Kloosterhof NK , RooiJJD , KrosMet al. Molecular subtypes of glioma identified by genome-wide methylation profiling . Genes Chromosomes Cancer52 , 665 – 674 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Kim T-M , HuangW , ParkRet al. A developmental taxonomy of glioblastoma defined and maintained by microRNAs . Cancer Res.71 , 3387 – 3399 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Brennan C , MomotaH , HambardzumyanDet al. Glioblastoma subclasses can be defined by activity among signal transduction pathways and associated genomic alterations . PLoS ONE4 , e7752 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Maleszewska M , KaminskaB . Is glioblastoma an epigenetic malignancy?Cancers5 , 1120 – 1139 ( 2013 ).
   PubMedGoogle Scholar
• Jones PA , BaylinSB . The epigenomics of cancer . Cell128 , 683 – 692 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Mariño-Ramírez L , KannMG , ShoemakerBA , LandsmanD . Histone structure and nucleosome stability . Expert Rev. Proteomics2 , 719 – 729 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• Kim YZ . Altered histone modifications in gliomas . Brain Tumor Res. Treat.2 , 7 – 21 ( 2014 ).
   PubMedGoogle Scholar
• Moreno NN , GionoLE , BottoAECet al. Chromatin, DNA structure and alternative splicing . FEBS Letters589 , 3370 – 3378 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Galvani A , ThirietC . Nucleosome dancing at the tempo of histone tail acetylation . Genes6 , 607 – 621 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Jenuwein T , AllisCD . Translating the histone code . Science293 , 1074 – 1080 ( 2001 ).
   PubMed Web of Science ®Google Scholar
• Parbin S , KarS , ShilpiAet al. Histone deacetylases: a saga of perturbed acetylation homeostasis in cancer . J. Histochem. Cytochem.62 , 11 – 33 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Zentner GE , HenikoffS . Regulation of nucleosome dynamics by histone modifications . Nat. Struct. Mol. Biol.20 , 259 – 266 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Wang Z , ZangC , CuiKet al. Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes . Cell138 , 1019 – 1031 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Kruhlak MJ , HendzelMJ , FischleWet al. Regulation of global acetylation in mitosis through loss of histone acetyltransferases and deacetylases from chromatin . J. Biol. Chem.276 , 38307 – 38319 ( 2001 ).
   PubMed Web of Science ®Google Scholar
• Montezuma D , HenriqueRMF , JeronimoC . Altered expression of histone deacetylases in cancer . Crit. Rev. Oncog.20 , 19 – 34 ( 2015 ).
   PubMedGoogle Scholar
• Ropero S , EstellerM . The role of histone deacetylases (HDACs) in human cancer . Mol. Oncol.1 , 19 – 25 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Barneda-Zahonero B , ParraM . Histone deacetylases and cancer . Mol. Oncol.6 , 579 – 589 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Tang J , YanH , ZhuangS . Histone deacetylases as targets for treatment of multiple diseases . Clin. Sci.124 , 651 – 662 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Mohseni J , Zabidi-HussinZ , SasongkoTH . Histone deacetylase inhibitors as potential treatment for spinal muscular atrophy . Genet. Mol. Biol.36 , 299 – 307 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Perry J , OkamotoM , GuiouM , ShiraiK , ErrettA , ChakravartiA . Novel therapies in glioblastoma . Neurol. Res. Int.2012 , 1 – 14 ( 2012 ).
   Google Scholar
• Friday BB , AndersonSK , BucknerJet 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 ).
   PubMed Web of Science ®Google Scholar
• Xu J , SampathD , LangFFet al. Vorinostat modulates cell cycle regulatory proteins in glioma cells and human glioma slice cultures . J. Neurooncol.105 , 241 – 251 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Orzan F , PellegattaS , PolianiPLet 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 ).
   PubMed Web of Science ®Google Scholar
• Xiao Y . Enhancer of zeste homolog 2: a potential target for tumor therapy . Int. J. Biochem. Cell. Biol.43 , 474 – 477 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Singh MM , JohnsonB , VenkatarayanAet al. Preclinical activity of combined HDAC and KDM1A inhibition in glioblastoma . Neuro Oncol.17 , 1463 – 1473 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Lee EQ , PuduvalliVK , ReidJMet 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 ).
   PubMed Web of Science ®Google Scholar
• Galanis E , JaeckleKA , MaurerMJet al. Phase II trial of vorinostat in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group study . J. Clin. Oncol.27 , 2052 – 2058 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Pont LMB , KleijnA , KloezemanJJet 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 ONE10 , e0127058 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Dokmanovic M , ClarkeC , MarksPA . Histone deacetylase inhibitors: overview and perspectives . Mol. Cancer Res.5 , 981 – 989 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Alvarez AA , FieldM , BushnevSet al. The effects of histone deacetylase inhibitors on glioblastoma-derived stem cells . J. Mol. Neurosci.55 , 7 – 20 ( 2015 ).
   PubMedGoogle Scholar
• Ekström T , AlmqvistP , SvechnikovaI . HDAC inhibitors effectively induce cell type-specific differentiation in human glioblastoma cell lines of different origin . Int. J. Oncol.32 , 821 – 827 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Höring E , PodlechO , SilkenstedtBet al. The histone deacetylase inhibitor trichostatin a promotes apoptosis and antitumor immunity in glioblastoma cells . Anticancer Res.33 , 1351 – 1360 ( 2013 ).
   PubMedGoogle Scholar
• Eisele G , WischhusenJ , MittelbronnMet al. TGF-beta and metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells . Brain129 , 2416 – 2425 ( 2006 ).
   PubMed Web of Science ®Google Scholar
• Armeanu S , BitzerM , LauerUMet al. Natural killer cell-mediated lysis of hepatoma cells via specific induction of NKG2D ligands by the histone deacetylase inhibitor sodium valproate . Cancer Res.65 , 6321 – 6329 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• Adamopoulou E , NaumannU . HDAC inhibitors and their potential applications to glioblastoma therapy . Oncoimmunology2 , e25219 ( 2013 ).
   PubMedGoogle Scholar
• Kusaczuk M , KrętowskiR , BartoszewiczMet al. Phenylbutyrate – a pan-HDAC inhibitor – suppresses proliferation of glioblastoma LN-229 cell line . Tumour Biol.1 – 12 ( 2015 ).
   Google Scholar
• Hazane-Puch F , ArnaudJ , TrocméCet al. Sodium selenite decreased HDAC activity, cell proliferation and induced apoptosis in three human glioblastoma cells . Anticancer Agents Med. Chem.16 , 490 – 500 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Gryder BE , SodjiQH , OyelereAK . Targeted cancer therapy: giving histone deacetylase inhibitors all they need to succeed . Future Med. Chem.4 , 505 – 524 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Bannister AJ , KouzaridesT . Regulation of chromatin by histone modifications . Cell Res.21 , 381 – 395 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Cheung P , LauP . Epigenetic regulation by histone methylation and histone variants . Mol. Endocrinol.19 , 563 – 573 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• Kooistra SM , HelinK . Molecular mechanisms and potential functions of histone demethylases . Nat. Rev. Mol. Cell Biol.13 , 297 – 311 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Creyghton MP , ChengAW , WelsteadGGet al. Histone H3K27ac separates active from poised enhancers and predicts developmental state . Proc. Natl Acad. Sci. USA107 , 21931 – 21936 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Liang G , LinJC , WeiVet al. Distinct localization of histone H3 acetylation and H3-K4 methylation to the transcription start sites in the human genome . Proc. Natl Acad. Sci. USA101 , 7357 – 7362 ( 2004 ).
   PubMed Web of Science ®Google Scholar
• Parsons DW , JonesS , ZhangXet al. An integrated genomic analysis of human glioblastoma multiforme . Science321 , 1807 – 1812 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Black JC , Van RechemC , WhetstineJR . Histone lysine methylation dynamics: establishment, regulation, and biological impact . Mol. Cell48 , 491 – 507 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Chan KM , FangD , GanHet al. The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression . Genes Dev.27 , 985 – 990 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Sturm D , WittH , HovestadtVet al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma . Cancer Cell22 , 425 – 437 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Bender S , TangY , LindrothAMet al. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas . Cancer Cell24 , 660 – 672 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Lewis PW , MüllerMM , KoletskyMSet al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma . Science340 , 857 – 861 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Nagarajan RP , ZhangB , BellRJet al. Recurrent epimutations activate gene body promoters in primary glioblastoma . Genome Res.24 , 761 – 774 ( 2014 ).
   PubMedGoogle Scholar
• Ott M , LitzenburgerUM , SahmFet al. Promotion of glioblastoma cell motility by enhancer of zeste homolog 2 (EZH2) is mediated by AXL receptor kinase . PLoS ONE7 , e47663 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Natsume A , ItoM , KatsushimaKet al. Chromatin regulator PRC2 is a key regulator of epigenetic plasticity in glioblastoma . Cancer Res.73 , 4559 – 4570 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Baldwin RM , MorettinA , CôtéJ . Role of PRMTs in cancer: could minor isoforms be leaving a mark?World J. Biol. Chem.5 , 115 – 129 ( 2014 ).
   PubMedGoogle Scholar
• Yan F , AlinariL , LustbergMEet al. Genetic validation of the protein arginine methyltransferase PRMT5 as a candidate therapeutic target in glioblastoma . Cancer Res.74 , 1752 – 1765 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Han X , LiR , ZhangWet 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 ).
   PubMed Web of Science ®Google Scholar
• Mongiardi MP , SavinoM , BartoliLet al. MYC and OMOMYC functionally associate with the protein arginine methyltransferase 5 (PRMT5) in glioblastoma cells . Sci. Rep.5 , 15494 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Banelli B , CarraE , BarbieriFet al. The histone demethylase KDM5A is a key factor for the resistance to temozolomide in glioblastoma . Cell Cycle14 , 3418 – 3429 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Cloos PA , ChristensenJ , AggerKet al. Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease . Genes Dev.22 , 1115 – 1140 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Ene CI , EdwardsL , RiddickGet al. Histone demethylase Jumonji D3 (JMJD3) as a tumor suppressor by regulating p53 protein nuclear stabilization . PLoS ONE7 , e51407 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Perrigue PM , SilvaME , WardenCDet al. The histone demethylase Jumonji coordinates cellular senescence including secretion of neural stem cell-attracting cytokines . Mol. Cancer Res.13 , 636 – 650 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Liu BL , ChengJX , ZhangXet al. Global histone modification patterns as prognostic markers to classify glioma patients . Cancer Epidemiol. Biomarkers Prev.19 , 2888 – 2896 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Kozono D , LiJ , NittaMet al. Dynamic epigenetic regulation of glioblastoma tumorigenicity through LSD1 modulation of MYC expression . Proc. Natl. Acad. Sci. USA112 , E4055 – E4064 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Costa BM , SmithJS , ChenYet al. Reversing HOXA9 oncogene activation by PI3K inhibition: epigenetic mechanism and prognostic significance in human glioblastoma . Cancer Res.70 , 453 – 462 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Alaminos M , DávalosV , RoperoSet al. Emp3, a myelin-related 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 ).
   PubMed Web of Science ®Google Scholar
• Hesson L , BiècheI , KrexDet al. Frequent epigenetic inactivation of RASSF1A and BLU genes located within the critical 3p21.3 region in gliomas . Oncogene23 , 2408 – 2419 ( 2004 ).
   PubMed Web of Science ®Google Scholar
• Malzkorn B , WolterM , RiemenschneiderMJet al. Unraveling the glioma epigenome: from molecular mechanisms to novel biomarkers and therapeutic targets . Brain Pathol.21 , 619 – 632 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Hyman G , ManglikV , RouschJMet al. Epigenetic approaches in glioblastoma multiforme and their implication in screening and diagnosis . Methos. Mol. Biol.1238 , 511 – 521 ( 2015 ).
   PubMedGoogle Scholar
• Dunn GP , RinneML , WykoskyJet al. Emerging insights into the molecular and cellular basis of glioblastoma . Genes Dev.26 , 756 – 784 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Stratton MR , CampbellP , FutrealP . The cancer genome . Nature458 , 719 – 724 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Esteller M . CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future . Oncogene21 , 5427 – 5440 ( 2002 ).
   PubMed Web of Science ®Google Scholar
• Wolf SF , JollyDJ , LunnenKDet al. Methylation of the hypoxanthine phosphoribosyltransferase locus on the human X chromosome: implications for X-chromosome inactivation . Proc. Natl Acad. Sci. USA81 ( 9 ), 2806 – 2810 ( 1984 ).
   PubMed Web of Science ®Google Scholar
• Agnihotri S , WolfA , MunozDMet al. A GATA4-regulated tumor suppressor network represses formation of malignant human astrocytomas . J. Exp. Med.208 , 689 – 702 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Tepel M , RoerigP , WolterMet al. Frequent promoter hypermethylation and transcriptional downregulation of the NDRG2 gene at 14q11.2 in primary glioblastoma . Int. J. Cancer123 ( 9 ), 2080 – 2086 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Nakamura M , WatanabeT , YonekawaYet 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 . Carcinogenesis22 , 1715 – 1719 ( 2001 ).
   PubMed Web of Science ®Google Scholar
• Eoli M , MenghiF , BruzzoneMGet 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 ).
   PubMed Web of Science ®Google Scholar
• Stone AR , BoboW , BratDJet al. Aberrant methylation and down-regulation of TMS1/ASC in human glioblastoma . Am. J. Pathol.165 , 1151 – 1161 ( 2004 ).
   PubMed Web of Science ®Google Scholar
• Kosla K , PluciennikE , KurzykAet al. Molecular analysis of WWOX expression correlation with proliferation and apoptosis in glioblastoma multiforme . J. Neurooncol.101 , 207 – 213 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Waha A , GüntnerS , HuangTHet al. Epigenetic silencing of the protocadherin family member PCDH-gamma-A11 in astrocytomas . Neoplasia7 , 193 – 199 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• Lindemann C , HackmannO , DelicSet 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 ).
   PubMed Web of Science ®Google Scholar
• Alonso MM , Diez-ValleR , ManterolaLet al. Genetic and epigenetic modifications of Sox2 contribute to the invasive phenotype of malignant gliomas . PLoS ONE6 , e26740 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Dubuc AM , MackS , UnterbergerAet al. The epigenetics of brain tumors. Methods in molecular biology cancer epigenetics . Methods Mol. Biol.863 , 139 – 153 ( 2012 ).
   PubMedGoogle Scholar
• Foltz G , RyuGY , YoonJGet 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 ).
   PubMed Web of Science ®Google Scholar
• Laffaire J , EverhardS , IdbaihAet al. Methylation profiling identifies 2 groups of gliomas according to their tumorigenesis . Neuro Oncol.13 , 84 – 98 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Martinez R , Martin-SuberoJI , RohdeVet al. A microarray-based DNA methylation study of glioblastoma multiforme . Epigenetics4 , 255 – 264 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Mueller W , NuttCL , EhrichMet al. Downregulation of RUNX3 and TES by hypermethylation in glioblastoma . Oncogene26 , 583 – 593 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Schmidt N , WindmannS , ReifenbergerGet al. DNA hypermethylation and histone modifications downregulate the candidate tumor suppressor gene RRP22 on 22q12 in human gliomas . Brain Pathol.22 , 17 – 25 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Bozdag S , LiA , RiddickGet al. Age-specific signatures of glioblastoma at the genomic, genetic, and epigenetic levels . PLoS ONE8 , e62982 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Etcheverry A , AubryM , TayracMDet al. DNA methylation in glioblastoma: impact on gene expression and clinical outcome . BMC Genomics11 , 701 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• McNamara MG , SahebjamS , MasonWP . Emerging biomarkers in glioblastoma . Cancers (Basel)5 , 1103 – 1119 ( 2013 ).
   PubMedGoogle Scholar
• Pegg AE . Repair of O(6)-alkylguanine by alkyltransferases . Mutat. Res.462 , 83 – 100 ( 2000 ).
   PubMed Web of Science ®Google Scholar
• Stupp R , HegiME , MasonWPet 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 EORTC-NCIC trial . Lancet Oncol.10 , 459 – 466 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Weller M , FelsbergJ , HartmannCet 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 ).
   PubMed Web of Science ®Google Scholar
• Riemenschneider MJ , HegiME , ReifenbergerG . MGMT promoter methylation inmalignant gliomas . Target Oncol.5 , 161 – 165 ( 2010 ).
   PubMedGoogle Scholar
• Ang C , GuiotMC , RamanakumarAVet al. Clinical significance of molecular biomarkers in glioblastoma . Can. J. Neurol. Sci.37 , 625 – 630 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Blanc JL , WagerM , GuilhotJet al. Correlation of clinical features and methylation status of MGMT gene promoter in glioblastomas . J. Neurooncol.68 , 275 – 283 ( 2004 ).
   PubMed Web of Science ®Google Scholar
• Bleeker FE , MolenaarRJ , LeenstraS . Recent advances in the molecular understanding of glioblastoma . J. Neurooncol.108 , 11 – 27 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Zawlik I , VaccarellaS , KitaDet al. Promoter methylation and polymorphisms of the MGMT gene in glioblastomas: a population-based study . Neuroepidemiology32 , 21 – 29 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Brennan CW , VerhaakRGW , McKennaAet al. The somatic genomic landscape of glioblastoma . Cell155 , 462 – 477 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Buckner JC , BallmanKV , MichalakJCet 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 ).
   PubMed Web of Science ®Google Scholar
• Halperin EC , HerndonJ , ScholdSCet 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 ).
   PubMed Web of Science ®Google Scholar
• Stewart LA . Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials . Lancet359 , 1011 – 1018 ( 2002 ).
   PubMed Web of Science ®Google Scholar
• Shen L , AhujaN , ShenYet al. DNA methylation and environmental exposures in human hepatocellular carcinoma . J. Natl Cancer Inst.94 , 755 – 761 ( 2002 ).
   PubMedGoogle Scholar
• Toyota M , AhujaN , Ohe-ToyotaMet al. CpG island methylator phenotype in colorectal cancer . Proc. Natl Acad. Sci. USA96 , 8681 – 8686 ( 1999 ).
   PubMed Web of Science ®Google Scholar
• Hinoue T , WeisenbergerDJ , LangeCPet al. Genome-scale analysis of aberrant DNA methylation in colorectal cancer . Genome Res.22 , 271 – 282 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Issa JP . CpG island methylator phenotype in cancer . Nat. Rev. Cancer4 , 988 – 993 ( 2004 ).
   PubMed Web of Science ®Google Scholar
• Toyota M , AhujaN , SuzukiHet al. Aberrant methylation in gastric cancer associated with the CpG island methylator phenotype . Cancer Res.59 , 5438 – 5442 ( 1999 ).
   PubMed Web of Science ®Google Scholar
• Suzuki M , ShigematsuH , IizasaTet al. Exclusive mutation in epidermal growth factor receptor gene, HER-2, and KRAS, and synchronous methylation of nonsmall cell lung cancer . Cancer106 , 2200 – 2207 ( 2006 ).
   PubMed Web of Science ®Google Scholar
• Ueki T , ToyotaM , SohnTet al. Hypermethylation of multiple genes in pancreatic adenocarcinoma . Cancer Res.60 , 1835 – 1839 ( 2000 ).
   PubMed Web of Science ®Google Scholar
• Strathdee G , AppletonK , IllandMet al. Primary ovarian carcinomas display multiple methylator phenotypes involving known tumor suppressor genes . Am. J. Pathol.158 , 1121 – 1127 ( 2001 ).
   PubMed Web of Science ®Google Scholar
• Roman-Gomez J , Jimenez-VelascoA , AgirreXet 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 ).
   PubMed Web of Science ®Google Scholar
• Turcan S , RohleD , GoenkaAet al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype . Nature483 , 479 – 483 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Mazor T , PankovA , JohnsonBEet al. DNA methylation and somatic mutations converge on the cell cycle and define similar evolutionary histories in brain tumors . Cancer Cell28 , 307 – 317 ( 2015 ).
   PubMedGoogle Scholar
• Baysan M , BozdagS , CamMCet al. G-cimp status prediction of glioblastoma samples using mRNA expression data . PLoS ONE7 , e47839 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• van den Bent MJ , GravendeelLA , GorliaTet 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 ).
   PubMed Web of Science ®Google Scholar
• Cadieux B , ChingTT , VandenBergSRet 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 ).
   PubMed Web of Science ®Google Scholar
• Jackson K , YuMC , ArakawaKet al. DNA hypomethylation is prevalent even in low-grade breast cancers . Cancer Biol. Ther.3 , 1225 – 1231 ( 2004 ).
   PubMed Web of Science ®Google Scholar
• Nagarajan RP , CostelloJF . Epigenetic mechanisms in glioblastoma multiforme . Semin. Cancer Biol.19 , 188 – 197 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Lai RK , ChenY , GuanXet al. Genome-wide methylation analyses in glioblastoma multiforme . PLoS ONE9 ( 2 ), e89376 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Alelú-Paz R1 , AshourN , González-CorpasAet al. DNA methylation, histone modifications, and signal transduction pathways: a close relationship in malignant gliomas pathophysiology . J. Signal. Transduct.2012 , 956958 ( 2012 ).
   PubMedGoogle Scholar
• Soroceanu L , KharbandaS , ChenRet al. Identification of IGF2 signaling through phosphoinositide-3-kinase regulatory subunit 3 as a growth-promoting axis in glioblastoma . Proc. Natl Acad. Sci. USA104 , 3466 – 3471 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Wang H , WangY , BaoZet al. Hypomethylated Rab27b is a progression-associated prognostic biomarker of glioma regulating MMP-9 to promote invasion . Oncol. Rep.34 , 1503 – 1509 ( 2015 ).
   PubMedGoogle Scholar
• Liu X , TangH , WangZet al. F10 gene hypomethylation, a putative biomarker for glioma prognosis . J. Neurooncol.107 , 479 – 485 ( 2012 ).
   PubMedGoogle Scholar
• Liu X , TangH , ZhangZet al. POTEH hypomethylation, a new epigenetic biomarker for glioma prognosis . Brain Res.1391 , 125 – 131 ( 2011 ).
   PubMedGoogle Scholar
• Alonso MM , Diez-ValleR , ManterolaLet al. Genetic and epigenetic modifications of Sox2 contribute to the invasive phenotype of malignant gliomas . PLoS ONE6 , e26740 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Shi J , ShiW , NiLet al. OCT4 is epigenetically regulated by DNA hypomethylation of promoter and exon in primary gliomas . Oncol. Rep.30 , 201 – 206 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Xiaoping L , ZhibinY , WenjuanLet al. CPEB1, a histone-modified hypomethylated gene, is regulated by miR-101 and involved in cell senescence in glioma . Cell Death Dis.4 , e675 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Kim VN . MicroRNA biogenesis: coordinated cropping and dicing . Nat. Rev. Mol. Cell. Biol.6 , 376 – 385 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• Lewis BP , BurgeCB , BartelDP . Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets . Cell120 , 15 – 20 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• Green D , DalmayT , ChapmanT . Microguards and micromessengers of the genome . Heredity (Edinb.)116 ( 2 ), 125 – 134 ( 2015 ).
   PubMedGoogle Scholar
• Dews M , HomayouniA , YuDet al. Augmentation of tumor angiogenesis by a MYC-activated microRNA cluster . Nat. Genet.38 , 1060 – 1065 ( 2006 ).
   PubMed Web of Science ®Google Scholar
• Kumar MS , LuJ , MercerKLet al. Impaired microRNA processing enhances cellular transformation and tumorigenesis . Nat. Genet.39 , 673 – 677 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Ohtsuka M , LingH , DokiYet al. MicroRNA processing and human cancer . J. Clin. Med.4 , 1651 – 1667 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Lu J , GetzG , MiskaEAet al. MicroRNA expression profiles classify human cancers . Nature435 , 834 – 838 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• Somasundaram K , RaoSAM , NawazZ . MicroRNA (miRNA) regulation in glioma: implications in development, progression, grading, prognosis and therapy . Molecular Targets of CNS Tumors. InTech , 686 ( 2011 ).
   Google Scholar
• Areeb Z , StylliSS , KoldejR , RitchieDSet al. MicroRNA as potential biomarkers in glioblastoma . J. Neurooncol.125 , 237 – 248 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Ciafre SA , GalardiS , MangiolaAet al. Extensive modulation of a set of microRNAs in primary glioblastoma . Biochem. Biophys. Res. Commun.334 , 1351 – 1358 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• Chan JA , KrichevskyAM , KosikKS . MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells . Cancer Res.65 , 6029 – 6033 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• Silber J , LimDA , PetritschCet 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 ).
   PubMed Web of Science ®Google Scholar
• Lages E , GuttinA , El AtifiMet al. MicroRNA and target protein patterns reveal physiopathological features of glioma subtypes . PLoS ONE6 ( 5 ), e20600 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Godlewski J , NowickiMO , BroniszAet 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 ).
   PubMed Web of Science ®Google Scholar
• Sasayama T , NishiharaM , KondohTet al. MicroRNA-10b is overexpressed in malignant glioma and associated with tumor invasive factors, uPAR and RhoC . Int. J. Cancer125 , 1407 – 1413 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Hua D , MoF , DingDet al. A catalogue of glioblastoma and brain microRNAs identified by deep sequencing . OMICS16 , 690 – 699 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Skalsky RL , CullenBR . Reduced expression of brain-enriched microRNAs in glioblastomas permits targeted regulation of a cell death gene . PLoS ONE6 , e24248 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Zhi F , ChenX , WangSet al. The use of hsa-miR-21, hsa-miR-181b and hsa-miR-106a as prognostic indicators of astrocytoma . Eur. J. Cancer46 , 1640 – 1649 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Qiu S , LinS , HuDet 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 ).
   PubMed Web of Science ®Google Scholar
• Zadran S , RemacleF , LevineR . Surprisal analysis of glioblastoma multiform (GBM) microRNA dynamics unveils tumor specific phenotype . PLoS ONE9 ( 9 ), e108171 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Piwecka M , RolleK , WyszkoEet al. Nucleic acid-based technologies in therapy of malignant gliomas . Curr. Pharm. Biotechnol.12 , 1805 – 1822 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Rolle K . miRNA multiplayers in glioma. From bench to bedside . Acta Biochim. Pol.62 , 353 – 365 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Srinivasan S , PatricIR , SomasundaramK . A ten-microRNA expression signature predicts survival in glioblastoma . PLoS ONE6 , e17438 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Zhang W , ZhangJ , YanWet al. Whole-genome microRNA expression profiling identifies a 5-microRNA signature as a prognostic biomarker in Chinese patients with primary glioblastoma multiforme . Cancer119 , 814 – 824 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Garzon R , MarcucciG , CroceCM . Targeting microRNAs in cancer: rationale, strategies and challenges . Nat. Rev. Drug Discov.9 , 775 – 789 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Gomes-da-Silva LC , FernándezY , AbasoloIet al. Efficient intracellular delivery of siRNA with a safe multitargeted lipid-based nanoplatform . Nanomedicine (Lond.)8 , 1397 – 1413 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Mizoguchi M , GuanY , YoshimotoKet al. Clinical implications of microRNAs in human glioblastoma . Front. Oncol.3 , 19 ( 2013 ).
   PubMedGoogle Scholar
• Mocellin S , PasqualiS , PilatiP . Oncomirs: from tumor biology to molecularly targeted anticancer strategies . Mini Rev. Med. Chem.9 , 70 – 80 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Anesti AM , SimpsonGR , PriceTet 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 Cancer10 , 486 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Santos AO , da SilvaLC , BimboLMet al. Design of peptide-targeted liposomes containing nucleic acids . Biochim. Biophys. Acta1798 , 433 – 441 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Ohno S , TakanashiM , SudoKet al. Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells . Mol. Ther.21 , 185 – 191 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Yan Y , ZhangL , JiangYet 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 ).
   PubMed Web of Science ®Google Scholar
• Prensner JR , ChinnaiyanAM . The emergence of lncRNAs in cancer biology . Cancer Discov.1 , 391 – 407 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Han L , ZhangK , ShiZet al. LncRNA profile of glioblastoma reveals the potential role of lncRNAs in contributing to glioblastoma pathogenesis . Int. J. Oncol.40 , 2004 – 2012 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Cao Y , WangP , NingSet 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 ).
   Google Scholar
• Li Y , WangZ , WangYet 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 ).
   Google Scholar
• Zhang K , SunX , ZhouXet al. Long non-coding RNA HOTAIR promotes glioblastoma cell cycle progression in an EZH2 dependent manner . Oncotarget1 , 537 – 546 ( 2014 ).
   Google Scholar
• Vassallo I , ZinnP , LaiMet al. WIF1 re-expression in glioblastoma inhibits migration through attenuation of non-canonical WNT signaling by downregulating the lncRNA MALAT1 . Oncogene35 , 12 – 21 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Yao Y , MaJ , XueYet 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 ).
   PubMed Web of Science ®Google Scholar
• Lathia JD , MackSC , Mulkearns-HubertEEet al. Cancer stem cells in glioblastoma . Genes Dev.29 , 1203 – 1217 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Bradshaw A , WickremsekeraA , TanSTet al. Cancer stem cell hierarchy in glioblastoma multiforme . Front. Surg.3 , 21 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Ignatova TN , KukekovVG , LaywellEDet al. Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro . Glia39 , 193 – 206 ( 2002 ).
   PubMed Web of Science ®Google Scholar
• Singh SK , ClarkeID , TerasakiMet al. Identification of a cancer stem cell in human brain tumors . Cancer Res.63 , 5821 – 5828 ( 2003 ).
   PubMed Web of Science ®Google Scholar
• Yuan X , CurtinJ , XiongYet al. Isolation of cancer stem cells from adult glioblastoma multiforme . Oncogene23 , 9392 – 9400 ( 2004 ).
   PubMed Web of Science ®Google Scholar
• Beier D , HauP , ProescholdtMet al. CD133 and CD133- glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles . Cancer Res.67 , 4010 – 4015 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Kelly JJP , StechishinO , ChojnackiAet al. Proliferation of human glioblastoma stem cells occurs independently of exogenous mitogens . Stem Cells27 , 1722 – 1733 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Piccirillo SG , BindaE , FioccoRet al. Brain cancer stem cells . J. Mol. Med. (Berl.)87 , 1087 – 1095 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Field M , AlvarezA , BushnevSet 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 ).
   PubMedGoogle Scholar
• Bhat KP , BalasubramaniyanV , VaillantBet al. Mesenchymal differentiation mediated by NF-κb promotes radiation resistance in glioblastoma . Cancer Cell24 , 331 – 346 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Mao P , JoshiK , LiJet al. Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3 . Proc. Natl Acad. Sci. USA110 , 8644 – 8649 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Codrici E , EnciuA-M , PopescuI-Det al. Glioma stem cells and their microenvironments: providers of challenging therapeutic targets . Stem Cells Int.2016 , 1 – 20 ( 2016 ).
   Web of Science ®Google Scholar
• Singh SK , HawkinsC , ClarkeIDet al. Identification of human brain tumour initiating cells . Nature432 , 396 – 401 ( 2004 ).
   PubMed Web of Science ®Google Scholar
• Gangemi RMR , GrifferoF , MarubbiDet al. SOX2 silencing in glioblastoma tumor-initiating cells causes stop of proliferation and loss of tumorigenicity . Stem Cells27 , 40 – 48 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Kalkan R . Glioblastoma stem cells as a new therapeutic target for glioblastoma . Clin. Med. Insights. Oncol.9 , 95 – 103 ( 2015 ).
   PubMedGoogle Scholar
• Olmez I , ShenW , McdonaldHet 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 ).
   PubMed Web of Science ®Google Scholar
• Zhang L , YanY , JiangYet 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 ).
   PubMed Web of Science ®Google Scholar
• Rahaman SO , HarborPC , ChernovaOet al. Inhibition of constitutively active Stat3 suppresses proliferation and induces apoptosis in glioblastoma multiforme cells . Oncogene21 , 8404 – 8413 ( 2002 ).
   PubMed Web of Science ®Google Scholar
• Li L , BhatiaR . Stem cell quiescence . Clin. Cancer Res.17 , 4936 – 4941 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Reya T , MorrisonSJ , ClarkeMFet al. Stem cells, cancer, and cancer stem cells . Nature414 , 105 – 111 ( 2001 ).
   PubMed Web of Science ®Google Scholar
• Vescovi AL , GalliR , ReynoldsBA . Brain tumour stem cells . Nat. Rev. Cancer6 , 425 – 436 ( 2006 ).
   PubMed Web of Science ®Google Scholar
• Bao S , WuQ , McLendonREet al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response . Nature444 , 756 – 760 ( 2006 ).
   PubMed Web of Science ®Google Scholar
• Rosen JM , JordanCT . The increasing complexity of the cancer stem cell paradigm . Science324 , 1670 – 1673 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Park DM , RichJN . Biology of glioma cancer stem cells . Mol. Cells28 , 7 – 12 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Heddleston JM , LiZ , LathiaJDet al. Hypoxia inducible factors in cancer stem cells . Br. J. Cancer102 , 789 – 795 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Frank NY , SchattonT , FrankMH . The therapeutic promise of the cancer stem cell concept . J. Clin. Invest.120 , 41 – 50 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Kanno H , MiyakeS , NakanowatariS . Signaling pathways in glioblastoma cancer stem cells: a role of Stat3 as a potential therapeutic target . Austin J. Cancer Clin. Res.2 , 1030 ( 2015 ).
   Google Scholar
• Jahani-Asl A , YinH , SoleimaniVDet al. Control of glioblastoma tumorigenesis by feed-forward cytokine signaling . Nat. Neurosci.19 , 798 – 806 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Smith AW , MehtaMP , WernickeAG . Neural stem cells, the subventricular zone and radiotherapy: implications for treating glioblastoma . J. Neurooncol.128 , 207 – 216 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Sanai N , Alvarez-BuyllaA , BergerMS . Neural stem cells and the origin of gliomas . N. Engl. J. Med.353 , 811 – 822 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• Barani IJ , BenedictSH , LinP-S . Neural stem cells: implications for the conventional radiotherapy of central nervous system malignancies . Int. J. Radiat. Oncol. Biol. Phys.68 , 324 – 333 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Kut C , RedmondKJ . New considerations in radiation treatment planning for brain tumors: neural progenitor cell-containing niches . Semin. Radiat. Oncol.24 , 265 – 272 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Wang J , WakemanTP , LathiaJDet al. Notch promotes radioresistance of glioma stem cells . Stem Cells28 , 17 – 28 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Liu G , YuanX , ZengZet al. Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma . Mol. Cancer5 , 67 ( 2006 ).
   PubMed Web of Science ®Google Scholar
• Lepinoux-Chambaud C , BarreauK , EyerJ . 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 ).
   PubMed Web of Science ®Google Scholar
• Seymour T , NowakA , KakulasF . Targeting aggressive cancer stem cells in glioblastoma . Front. Oncol.5 , 159 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Eramo A , Ricci-VitianiL , ZeunerAet al. Chemotherapy resistance of glioblastoma stem cells . Cell Death Differ.13 , 1238 – 1241 ( 2006 ).
   PubMed Web of Science ®Google Scholar
• Xu ZY , WangK , LiXQet al. The ABCG2 transporter is a key molecular determinant of the efficacy of sonodynamic therapy with Photofrin in glioma stem-like cells . Ultrasonics53 , 232 – 238 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Li WQ , LiYM , TaoBBet al. Downregulation of ABCG2 expression in glioblastoma cancer stem cells with miRNA-328 may decrease their chemoresistance . Med. Sci. Monit.16 , HY27 – HY30 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Bleau A-M , HambardzumyanD , OzawaTet al. PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells . Cell Stem Cell4 , 226 – 235 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Yu Z , ZhaoG , XieGet al. Metformin and temozolomide act synergistically to inhibit growth of glioma cells and glioma stem cells in vitro and in vivo . Oncotarget6 , 32930 – 32943 ( 2015 ).
   PubMedGoogle Scholar
• Shi L , ZhangS , FengKet 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 ).
   PubMed Web of Science ®Google Scholar
• Liebelt BD , ShinguT , ZhouXet al. Glioma stem cells: signalling, microenvironment, and therapy . Stem Cells Int.2016 , 7849890 ( 2016 ).
   PubMed Web of Science ®Google Scholar