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Special Focus: Pediatric Neuro-Oncology |
1 Department of Pediatrics, University of Iowa, Iowa City, IA 52242
2 Department of Neurosurgery, University of Iowa, Iowa City, IA 52242 and Institute for Systems Biology, 1441 North 34th St, Seattle, WA 98103
3 Department of Neurosurgery, University of Iowa, Iowa City, IA 52242
4 Department of Internal Medicine, University of Iowa, Iowa City, IA 52242
5 Department of Neurosurgery, University of Iowa, Iowa City, IA 52242 and Institute for Systems Biology, 1441 North 34th St, Seattle, WA 98103
* To whom correspondence should be addressed. E-mail: 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.
Key Words: histone deacetylation, Dickkopf-1, medulloblastoma, epigenetic, tumor suppressor
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