Abstract
Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements, the molecular mechanisms driving medulloblastoma are not fully understood and further elucidation could provide cues to improve outcome prediction and therapeutic approaches. Here, we conducted a meta-analysis of mouse and human medulloblastoma gene expression data sets, to identify potential medulloblastoma tumor suppressor genes. We identified DAB2IP, a member of the RAS-GTPase-activating protein family (RAS GAP), and showed that DAB2IP expression is repressed in medulloblastoma by EZH2-induced trimethylation. Moreover, we observed that reduced DAB2IP expression correlates significantly with a poor overall survival of patients with medulloblastoma, independent of metastatic stage. Finally, we showed that ectopic DAB2IP expression enhances stress-induced apoptosis in medulloblastoma cells and that reduced expression of DAB2IP in medulloblastoma cells conveys resistance to irradiation-induced cell death. These results suggest that repression of DAB2IP may at least partly protect medulloblastoma cells from apoptotic cell death. Moreover, DAB2IP may represent a molecular marker to distinguish patients with medulloblastoma at high risk from those with a longer survival prognosis.
Highlights
Brain tumors are the most common form of solid tumors in children of which medulloblastoma is the most frequent malignant variant, accounting for 20% of cases [1]
We found DAB2IP expression to be strongly downregulated in human medulloblastoma cells and in primary human medulloblastoma tissues
We show that DAB2IP downregulation is—at least partially—caused by EZH2-mediated repression through histone methylation, conveying apoptosis resistance in immortalized neural precursor and medulloblastoma cells
Summary
Brain tumors are the most common form of solid tumors in children of which medulloblastoma is the most frequent malignant variant, accounting for 20% of cases [1]. 4 subtypes: WNT, SHH, group 3, and group 4, which differ regarding histology and clinical outcome [4] and are believed to derive from the deregulation of various signaling pathways in brain development, such as the WNT-pathway and sonic hedgehog (SHH) signaling pathways. Overactivation of these pathways leads to a loss of cell-cycle control and a dysfunctional apoptosis program, allowing for continued growth and tumorigenesis, predominantly in the cerebellum [5]
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