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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).

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.

Key Words: Dickkopf-1 • epigenetic • histone deacetylation • medulloblastoma • tumor suppressor

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