title: Dickkopf-1 is an epigenetically silenced candidate tumor suppressor gene in medulloblastoma.
abstract: Medulloblastoma is a heterogeneous pediatric brain tumor with significant therapy-related morbidity, its five-year survival rates ranging from 30% to 70%. Improvement in diagnosis and therapy requires better understanding of medulloblastoma pathology. We used whole-genome microarray analysis to identify putative tumor suppressor genes silenced by epigenetic mechanisms in medulloblastoma. This analysis yielded 714 up-regulated genes in immortalized medulloblastoma cell line D283 on treatment with histone deacetylase (HDAC) inhibitor trichostatin A (TSA). Dickkopf-1 (DKK1), a Wnt antagonist, was found to be up-regulated on HDAC inhibition. We examined DKK1 expression in primary medulloblastoma cells and patient samples by reverse transcriptase PCR and found it to be significantly down-regulated relative to normal cerebellum. Transfection of a DKK1 gene construct into D283 cell lines suppressed medulloblastoma tumor growth in colony focus assays by 60% (P < 0.001). In addition, adenoviral vector-mediated expression of DKK1 in medulloblastoma cells increased apoptosis fourfold (P < 0.001). These data reveal that inappropriate histone modifications might deregulate DKK1 expression in medulloblastoma tumorigenesis and block its tumor-suppressive activity.
authors.affiliation: Department of Pediatric, University of Iowa, Iowa City, IA 52242, USA. Rajeev-Vibhakar@uiowa.edu
authors.forename: Rajeev
authors.initials: R
authors.lastname: Vibhakar
authors.forename: Greg
authors.initials: G
authors.lastname: Foltz
authors.forename: Jae-Geun
authors.initials: JG
authors.lastname: Yoon
authors.forename: Lorie
authors.initials: L
authors.lastname: Field
authors.forename: Hwahyung
authors.initials: H
authors.lastname: Lee
authors.forename: Gi-Yung
authors.initials: GY
authors.lastname: Ryu
authors.forename: Jessica
authors.initials: J
authors.lastname: Pierson
authors.forename: Beverly
authors.initials: B
authors.lastname: Davidson
authors.forename: Anup
authors.initials: A
authors.lastname: Madan
mesh_terms: D002455:Cell Division / Q000187:drug effects; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000401:mortality; D002843:Chromatin / Q000235:genetics; D003114:Colony-Forming Units Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008527:Medulloblastoma / Q000235:genetics* / Q000401:mortality; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D014407:Tumor Cells, Cultured
chemical_list: D002843:Chromatin; C501126:DKK1 protein, human; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D036341:Intercellular Signaling Peptides and Proteins; C012589:trichostatin A