Dickkopf-1 is an epigenetically silenced candidate tumor suppressor gene in medulloblastoma1
Departments of Pediatrics (R.V., J.P.), Neurosurgery (G.F., J.Y., L.F., H.L., G.R., A.M.), and Internal Medicine (B.D.), University of Iowa, Iowa City, IA 52242; Institute for Systems Biology, Seattle, WA 98103 (G.F., A.M.); USA
2 Address correspondence to Rajeev Vibhakar, M.D., Ph.D., Pediatric Hematology-Oncology, University of Iowa, Iowa City, IA 52242 (Rajeev-Vibhakar{at}uiowa.edu).
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Abstract |
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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.
Keywords: Dickkopf-1, epigenetic, histone deacetylation, medulloblastoma, tumor suppressor
Received July 14, 2006; Accepted August 25, 2006
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