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

Abstract

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.Experimental Design: Here, we conducted a meta-analysis of mouse and human medulloblastoma 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 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.Conclusion: 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.

Block one, unleash a hundred. Mechanisms of DAB2IP inactivation in cancer

“…15,65 Molecular studies on the TSS in exon 3 confirmed that high levels of di-and tri-methyl H3-Lys27 in this region are directly modulated by EZH2, leading to recruitment of the PRC2 protein complex and histone deacetylases HDAC1/2. 42,65,68 In line with methylation-driven epigenetic silencing, treatment with 5′-aza-cytidine and Trichostatin A cooperatively increased DAB2IP expression in cancer cell lines. 60 Recently, it has been reported that the transcription factor Snail can repress DAB2IP expression in colon cancer cells.…”

Roles of enhancer of zeste homolog 2: From skeletal muscle differentiation to rhabdomyosarcoma carcinogenesis

“…47,54 Additionally, EZH2 inhibits other tumor suppressor genes and microRNAs, such as p21, phosphatase and tensin homolog (PTEN), DAB2IP, Bim, and miR-31 in various human cancers. [108][109][110][111][112][113] Finally, several differentiation-related factors are PRC2-target genes, for instance, Gata, Sox, Fox, Pou, Pax, components of Wnt, TGF-β, Notch, FGF, and retinoic acid pathways. The EZH2-dependent silencing of these factors inhibits differentiation and promotes carcinogenesis.…”

Enhancer of Zeste Homolog 2 Expression Is Associated With Metastasis and Adverse Clinical Outcome in Clear Cell Renal Cell Carcinoma: A Comparative Study and Review of the Literature

“…71 Furthermore, EZH2 mediates epigenetic silencing of the promoters of DAB2IP, a crucial inhibitory modulator of oncogenic Ras-mediated signaling, which ultimately promotes tumor growth and induces metastasis in prostate cancer cell lines. [72][73][74][75] In anaplastic thyroid cancer cell lines, EZH2 directly prevents cell growth inhibition and differentiation by silencing the thyroidspecific transcription factor paired box gene 8 (PAX8).…”