title: Downregulation of PRDX1 by promoter hypermethylation is frequent in 1p/19q-deleted oligodendroglial tumours and increases radio- and chemosensitivity of Hs683 glioma cells in vitro.
abstract: Deletions of chromosomal arms 1p and 19q are frequent in oligodendroglial tumours and linked to radio- and chemotherapy response as well as longer survival. The molecular mechanisms underlying this clinically important association are as yet unknown. Here, we studied the peroxiredoxin 1 (PRDX1) gene at 1p34.1 for promoter methylation and expression in primary gliomas and investigated its role in radio- and chemosensitivity of glioma cells in vitro. In total, we screened primary glioma tissues from 93 patients for methylation of the 5'-CpG island of PRDX1 by sodium bisulfite sequencing. PRDX1 mRNA and protein expression levels were determined in subsets of the tumours by quantitative PCR and western blot analysis, respectively. PRDX1 hypermethylation and reduced expression were frequently detected in oligodendroglial tumours and secondary glioblastomas, but not in primary glioblastomas. In oligodendroglial tumours, both PRDX1 hypermethylation and reduced mRNA expression were significantly associated with 1p/19q-deletion. Stable knockdown of PRDX1 by lentiviral transduction of short-hairpin (sh)RNA constructs significantly increased apoptosis and reduced cell viability of Hs683 glioma cells exposed to ionizing irradiation or temozolomide in vitro. Taken together, our findings indicate that epigenetic silencing of PRDX1 is frequent in 1p/19q-deleted oligodendroglial tumours and likely contributes to radio- and chemosensitivity of these tumours.
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: L M
authors.initials: LM
authors.lastname: Dittmann
authors.forename: A
authors.initials: A
authors.lastname: Danner
authors.forename: J
authors.initials: J
authors.lastname: Gronych
authors.forename: M
authors.initials: M
authors.lastname: Wolter
authors.forename: K
authors.initials: K
authors.lastname: Stühler
authors.forename: M
authors.initials: M
authors.lastname: Grzendowski
authors.forename: N
authors.initials: N
authors.lastname: Becker
authors.forename: J
authors.initials: J
authors.lastname: Bageritz
authors.forename: V
authors.initials: V
authors.lastname: Goidts
authors.forename: G
authors.initials: G
authors.lastname: Toedt
authors.forename: J
authors.initials: J
authors.lastname: Felsberg
authors.forename: M C
authors.initials: MC
authors.lastname: Sabel
authors.forename: S
authors.initials: S
authors.lastname: Barbus
authors.forename: G
authors.initials: G
authors.lastname: Reifenberger
authors.forename: P
authors.initials: P
authors.lastname: Lichter
authors.forename: B
authors.initials: B
authors.lastname: Tews
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects / Q000528:radiation effects; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D054464:Peroxiredoxins / Q000172:deficiency / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D011836:Radiation Tolerance / Q000235:genetics*; D000077204:Temozolomide; D055815:Young Adult
chemical_list: D003606:Dacarbazine; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; C515940:PRDX1 protein, human; D054464:Peroxiredoxins; D000077204:Temozolomide