title: Epigenetically mediated downregulation of the differentiation-promoting chaperon protein CRABP2 in astrocytic gliomas.
abstract: Impairment of endogenous differentiation pathways like retinoic acid (RA) signaling seems to be a central pathogenetic event in astrocytic gliomas. Among others, expression of the differentiation-promoting RA chaperon protein cellular retinoic acid binding protein 2 (CRABP2) is extenuated in high-grade gliomas. Against this background, we aimed at identifying potential pathomechanisms underlying reduced CRABP2 expression in these tumors. Using MassARRAY methylation analysis, we detected extensive CpG methylation upstream of the CRABP2 gene locus in a study sample comprising 100 astrocytic gliomas of WHO Grade II to IV. Compared to nontumorous control samples, tumors revealed increased CpG methylation and methylation levels were inversely correlated to CRABP2 mRNA expression. Substantiating our in situ findings, CRABP2 mRNA levels increased in glioma cell lines after exposure to the demethylating agent 5-aza-2'-deoxycytidine. Finally, a distinct CpG methylation signature distinguished between primary glioblastoma on the one hand and the group of astrocytoma WHO II-III and secondary glioblastoma on the other hand. Altogether, our observations suggest that epigenetic silencing of CRABP2 might contribute to an immature phenotype in glioma cells.
authors.affiliation: Division of Neurosurgical Research, Department of Neurosurgery, University of Heidelberg, INF 400, Heidelberg, Germany.
authors.forename: Benito
authors.initials: B
authors.lastname: Campos
authors.forename: Rolf
authors.initials: R
authors.lastname: Warta
authors.forename: Jittiporn
authors.initials: J
authors.lastname: Chaisaingmongkol
authors.forename: Lea
authors.initials: L
authors.lastname: Geiselhart
authors.forename: Odilia
authors.initials: O
authors.lastname: Popanda
authors.forename: Christian
authors.initials: C
authors.lastname: Hartmann
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.forename: Andreas
authors.initials: A
authors.lastname: Unterberg
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.forename: Peter
authors.initials: P
authors.lastname: Schmezer
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
mesh_terms: D001254:Astrocytoma / Q000235:genetics*; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D002454:Cell Differentiation; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D060787:Neoplasm Grading; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D018168:Receptors, Retinoic Acid; C082928:retinoic acid binding protein II, cellular; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human