Dickkopf-1 is an epigenetically silenced candidate tumor suppressor gene in medulloblastoma.
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.
Vibhakar
Rajeev
R
Department of Pediatric, University of Iowa, Iowa City, IA 52242, USA. Rajeev-Vibhakar@uiowa.edu
Foltz
Greg
G
Yoon
Jae-Geun
JG
Field
Lorie
L
Lee
Hwahyung
H
Ryu
Gi-Yung
GY
Pierson
Jessica
J
Davidson
Beverly
B
Madan
Anup
A
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
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