Dickkopf-1 is an epigenetically silenced candidate tumor suppressor gene in medulloblastoma.
Neuro Oncol
; 9(2): 135-44, 2007 Apr.
Article
en En
| MEDLINE
| ID: mdl-17329407
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Regulación Neoplásica de la Expresión Génica
/
Neoplasias Cerebelosas
/
Genes Supresores de Tumor
/
Péptidos y Proteínas de Señalización Intercelular
/
Meduloblastoma
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Neuro Oncol
Asunto de la revista:
NEOPLASIAS
/
NEUROLOGIA
Año:
2007
Tipo del documento:
Article
País de afiliación:
Estados Unidos