Human Cancer Biology EZH2-Regulated DAB2IP Is a Medulloblastoma Tumor Suppressor and a Positive Marker for Survival

Purpose: 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. ExperimentalDesign:Here, we conducted ameta-analysis ofmouse and humanmedulloblastoma gene expression data sets, to identify potential medulloblastoma tumor suppressor genes. Results: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 withmedulloblastoma, independent ofmetastatic stage. Finally, we showed that ectopicDAB2IP expression enhances stress-induced apoptosis in medulloblastoma cells and that reduced expression of DAB2IP in medulloblastoma cells conveys resistance to irradiation-induced cell death. Conclusion: These results suggest that repression ofDAB2IPmay at least partly protectmedulloblastoma cells from apoptotic cell death.Moreover, DAB2IPmay represent amolecularmarker to distinguish patients with medulloblastoma at high risk from those with a longer survival prognosis. Clin Cancer Res; 1–11.