Epigenetic deregulation of multiple S100 gene family members by differential hypomethylation and hypermethylation events in medulloblastoma

Abstract

Deregulated expression of genes encoding members of the S100 family of calcium-binding proteins has been associated with the malignant progression of multiple tumour types. Using a pharmacological expression reactivation approach, we screened 16 S100 genes for evidence of epigenetic regulation in medulloblastoma, the most common malignant brain tumour of childhood. Four family members (S100A2, S100A4, S100A6 and S100A10) demonstrated evidence of upregulated expression in multiple medulloblastoma cell lines, following treatment with the DNA methyltransferase inhibitor, 5 0 -aza-2 0 -deoxycytidine. Subsequent analysis revealed methylation of critical CpG sites located within these four genes in an extended cell line panel. Assessment of these genes in the nonneoplastic cerebellum (from which medulloblastomas develop) revealed strong somatic methylation affecting S100A2 and S100A4, whereas S100A6 and S100A10 were unmethylated. Assessed against these normal tissue-specific methylation states, S100A6 and S100A10 demonstrated tumour-specific hypermethylation in medulloblastoma primary tumours (5 out of 40 and 4 out of 35, respectively, both 12%) and cell lines (both 7 out of 9, 78%), which was associated with their transcriptional silencing. Moreover, S100A6 hypermethylation was significantly associated with the aggressive large cell/anaplastic morphophenotype (P ¼ 0.026). In contrast, pro-metastatic S100A4 displayed evidence of hypomethylation relative to the normal cerebellum in a significant proportion primary tumours (7 out of 41, 17%) and cell lines (3 out of 9, 33%), which was associated with its elevated expression. In summary, these data characterise complex patterns of somatic methylation affecting S100 genes in the normal cerebellum and demonstrate their disruption causing epigenetic deregulation of multiple S100 family members in medulloblastoma development. Epigenetic events affecting S100 genes have potential clinical utility and merit further investigation as molecular biomarkers for this disease.

Swedish mutation within amyloid precursor protein modulates global gene expression towards the pathogenesis of Alzheimer's disease

“…Besides the direct role of AICD as a transcription factor, epigenetic regulation including DNA methylation and histone modification might explain the global gene expression by APP-swe mutant. Recent studies have shown that an expression of S100 protein family is regulated by DNA methylation (26), and demethylating agent improved cognitive function in an animal model.…”

“…The expression of S100 protein family including S100A2, S100A4, S100A6, and S100A10 has been demonstrated to be largely dependent on CpG methylation (26). We tested the global DNA methylation pattern with H4 wt and H4-swe cell lines.…”

Additive Effects of 5-Aza-2’-deoxycytidine and Irradiation on Clonogenic Survival of Human Medulloblastoma Cell Lines

“…These results together with low induction of RASSF1a expression and data from Lindsey at al. [23,24] indicate that high dos- Abbildung 4. Dosis-Effekt-Kurven nach 5-aza-dC-Behandlung und/oder Bestrahlung.…”

Investigation of chromosome 1q reveals differential expression of members of the S100 family in clinical subgroups of intracranial paediatric ependymoma

“…S100A10, S100A6, S100A4 and S100A2 are all members of the S100 family of calcium-binding proteins and are located in a cluster on 1q21.3; a region that has been shown to have both high level gains (1q21 -q31; Ward et al, 2001) and an association with tumour recurrence in ependymoma (1q21.1 -q23.1; Mendrzyk et al, 2006). Members of the S100 family show divergent expression patterns in a range of tissues and several have been linked with cancer, including medulloblastoma (Hernan et al, 2003;Lindsey et al, 2007) and astrocytoma (Camby et al, 1999(Camby et al, , 2000. S100A6 has been shown to clearly distinguish between low (WHO grade I and II) and high (WHO grade III and IV) grade astrocytic tumours (Camby et al, 1999).…”