title: Epigenetic Silencing of DKK3 in medulloblastoma.
abstract: Medulloblastoma (MB) is a malignant pediatric brain tumor arising in the cerebellum consisting of four distinct subgroups: WNT, SHH, Group 3 and Group 4, which exhibit different molecular phenotypes. We studied the expression of Dickkopf (DKK) 1-4 family genes, inhibitors of the Wnt signaling cascade, in MB by screening 355 expression profiles derived from four independent datasets. Upregulation of DKK1, DKK2 and DKK4 mRNA was observed in the WNT subgroup, whereas DKK3 was downregulated in 80% MBs across subgroups with respect to the normal cerebellum (p < 0.001). Since copy number aberrations targeting the DKK3 locus (11p15.3) are rare events, we hypothesized that epigenetic factors could play a role in DKK3 regulation. Accordingly, we studied 77 miRNAs predicting to repress DKK3; however, no significant inverse correlation between miRNA/mRNA expression was observed. Moreover, the low methylation levels in the DKK3 promoters (median: 3%, 5% and 5% for promoter 1, 2 and 3, respectively) excluded the downregulation of gene expression by methylation. On the other hand, the treatment of MB cells with Trichostatin A (TSA), a potent inhibitor of histone deacetylases (HDAC), was able to restore both DKK3 mRNA and protein. In conclusion, DKK3 downregulation across all MB subgroups may be due to epigenetic mechanisms, in particular, through chromatin condensation.
authors.affiliation: Department of Experimental Medicine (DIMES), University of Genoa-IRCCS A.O.U. San Martino-IST National Cancer Research Institute, Genoa 16132, Italy. gptonini@gmail.com.
authors.forename: Francesca
authors.initials: F
authors.lastname: Valdora
authors.forename: Barbara
authors.initials: B
authors.lastname: Banelli
authors.forename: Sara
authors.initials: S
authors.lastname: Stigliani
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.forename: Stefano
authors.initials: S
authors.lastname: Moretti
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.forename: Alfa H C
authors.initials: AH
authors.lastname: Bai
authors.forename: Claudio
authors.initials: C
authors.lastname: Brigati
authors.forename: Thomas
authors.initials: T
authors.lastname: Hielscher
authors.forename: Massimo
authors.initials: M
authors.lastname: Romani
authors.forename: Tiziana
authors.initials: T
authors.lastname: Servidei
authors.forename: Massimo
authors.initials: M
authors.lastname: Zollo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cinalli
authors.forename: André
authors.initials: A
authors.lastname: Oberthuer
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Tonini
authors.forename: Simona
authors.initials: S
authors.lastname: Coco
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D018925:Chemokines; D002648:Child; D002675:Child, Preschool; D042002:Chromatin Assembly and Disassembly; D030541:Databases, Genetic; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007223:Infant; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008745:Methylation; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; C498624:DKK3 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm