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Vibhakar, R. et al.

Rajeev Vibhakar, Greg Foltz, Jae-Geun Yoon, Lorie Field, Hwahyung Lee, Gi-Yung Ryu, Jessica Pierson, Beverly Davidson, Anup Madan,

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.[1]

References

Dickkopf-1 is an epigenetically silenced candidate tumor suppressor gene in medulloblastoma. Vibhakar, R., Foltz, G., Yoon, J.G., Field, L., Lee, H., Ryu, G.Y., Pierson, J., Davidson, B., Madan, A. Neuro-oncology (2007) [Pubmed]

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