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Medulloblastoma (MB) are the most aggressive primary malignant brain tumors in children and are classified into four major molecular subgroups. WNT-MB is characterized by an activated WNT signature and has relatively better prognosis with treatment. However, young WNT-MB patients who survive after conventional treatment suffer from long-term irreversible neurocognitive and endocrine side effects leading to poor quality of life. ADGRB3 is a member of the ADGRB1-3 subfamily of adhesion GPCR transmembrane proteins, which are highly expressed in the cerebellum and hippocampal neurons. Our recent analysis of RNA-seq data from a published panel of MB tumor samples and RT-PCR experiments with tumor samples showed that ADGRB3 mRNA expression is selectively repressed in WNT-MB tumors compared to the other molecular subgroups and normal human cerebellum. We detected hypermethylation of the ADGRB3 promoter exclusively in WNT-MB samples. ChIP assays revealed enrichment of repressive methyl CpG binding MBD2 protein and trimethylated histone H3K9me3 in the ADGRB3 promoter region. We found that ATP dependent chromatin remodeler protein BRG-1 regulates ADGRB3 expression through epigenetic reprogramming at the gene promoter. Lentiviral reconstitution of ADGRB3 inhibited growth and WNT signaling in UW288-1, and PFSK-1 cells in culture. ADGRB3 reconstitution in UW288-1 MB cells causes a significant reduction in tumor growth and WNT target gene activation in orthotopic xenografts in nude mice. Furthermore, we found that ADGRB3 reactivation could be achieved using a blood brain barrier permeable MBD2 antagonist and an EZH2 inhibitor and this can significantly reduce cell growth and inhibit WNT signaling targets. Altogether, our findings define an epigenetic mechanism for ADGRB3 silencing in WNT-MB and demonstrated that reactivation of ADGRB3 can prevent WNT-MB tumor growth by suppressing WNT signaling. Our study supports translating epigenetic reactivation of ADGRB3 as a novel therapeutic intervention for children affected with WNT-MB.

PDTM-12. ADGRB3 IS EPIGENETICALLY SILENCED IN WNT-MEDULLOBLASTOMA AND ITS REACTIVATION HAS THERAPEUTIC BENEFITS