title: Identification of Global DNA Methylation Signatures in Glioblastoma-Derived Cancer Stem Cells.
abstract: Glioblastoma (GBM) is the most common and most aggressive primary brain tumor in adults. The existence of a small population of stem-like tumor cells that efficiently propagate tumors and resist cytotoxic therapy is one proposed mechanism leading to the resilient behavior of tumor cells and poor prognosis. In this study, we performed an in-depth analysis of the DNA methylation landscape in GBM-derived cancer stem cells (GSCs). Parallel comparisons of primary tumors and GSC lines derived from these tumors with normal controls (a neural stem cell (NSC) line and normal brain tissue) identified groups of hyper- and hypomethylated genes that display a trend of either increasing or decreasing methylation levels in the order of controls, primary GBMs, and their counterpart GSC lines, respectively. Interestingly, concurrent promoter hypermethylation and gene body hypomethylation were observed in a subset of genes including MGMT, AJAP1 and PTPRN2. These unique DNA methylation signatures were also found in primary GBM-derived xenograft tumors indicating that they are not tissue culture-related epigenetic changes. Integration of GSC-specific epigenetic signatures with gene expression analysis further identified candidate tumor suppressor genes that are frequently down-regulated in GBMs such as SPINT2, NEFM and PENK. Forced re-expression of SPINT2 reduced glioma cell proliferative capacity, anchorage independent growth, cell motility, and tumor sphere formation in vitro. The results from this study demonstrate that GSCs possess unique epigenetic signatures that may play important roles in the pathogenesis of GBM.
authors.affiliation: GRU Cancer Center, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Eun-Joon
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Department of Biology, College of Art and Sciences, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Prakash
authors.initials: P
authors.lastname: Rath
authors.affiliation: GRU Cancer Center, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Jimei
authors.initials: J
authors.lastname: Liu
authors.affiliation: GRU Cancer Center, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Dungsung
authors.initials: D
authors.lastname: Ryu
authors.affiliation: GRU Cancer Center, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Lirong
authors.initials: L
authors.lastname: Pei
authors.affiliation: GRU Cancer Center, Georgia Regents University, Augusta, GA 30912, USA; Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Satish K
authors.initials: SK
authors.lastname: Noonepalle
authors.affiliation: GRU Cancer Center, Georgia Regents University, Augusta, GA 30912, USA; Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Austin Y
authors.initials: AY
authors.lastname: Shull
authors.affiliation: Division of Neurological Surgery, University of Missouri School of Medicine, Columbia, MO 65211, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Feng
authors.affiliation: Division of Neurological Surgery, University of Missouri School of Medicine, Columbia, MO 65211, USA.
authors.forename: N Scott
authors.initials: NS
authors.lastname: Litofsky
authors.affiliation: Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine, Columbia, MO 65211, USA.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Miller
authors.affiliation: Department of Pathology and Laboratory Medicine, Brown University and Lifespan Academic Medical Center, Providence, RI 02903, USA.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Anthony
authors.affiliation: Department of Biology, College of Art and Sciences, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Kirk
authors.affiliation: Department of Neurology, The Hugo W. Moser Research Institute at Kennedy Krieger Inc. and The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: John
authors.initials: J
authors.lastname: Laterra
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang 330031, China.
authors.forename: Libin
authors.initials: L
authors.lastname: Deng
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang 330031, China.
authors.forename: Hong-Bo
authors.initials: HB
authors.lastname: Xin
authors.affiliation: David H. Murdock Research Institute, Kannapolis, NC 28081, USA.
authors.forename: Xinguo
authors.initials: X
authors.lastname: Wang
authors.affiliation: GRU Cancer Center, Georgia Regents University, Augusta, GA 30912, USA; Department of Biostatistics and Epidemiology, Georgia Regents University, Augusta, GA 30912, USA. Electronic address: jechoi@gru.edu.
authors.forename: Jeong-Hyeon
authors.initials: JH
authors.lastname: Choi
authors.affiliation: GRU Cancer Center, Georgia Regents University, Augusta, GA 30912, USA; Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA 30912, USA. Electronic address: hshi@gru.edu.
authors.forename: Huidong
authors.initials: H
authors.lastname: Shi
mesh_terms: D015815:Cell Adhesion Molecules / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D016900:Neurofilament Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: C483313:AJAP1 protein, human; D015815:Cell Adhesion Molecules; D008562:Membrane Glycoproteins; D016900:Neurofilament Proteins; C109148:SPINT2 protein, human; D025521:Tumor Suppressor Proteins; C061195:neurofilament protein M; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C102889:PTPRN2 protein, human; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D045643:DNA Repair Enzymes
keywords: Cancer stem cells; DNA methylation; Glioblastoma; SPINT2