CS-38 * BAI1 IS A NEW TUMOR SUPPRESSOR IN MEDULLOBLASTOMA

Abstract

Brain-specific Angiogenesis Inhibitor 1 (BAI1) is a seven transmembrane G protein-coupled receptor (GPCR) with potent anti-angiogenic and anti-tumorigenic properties in gliomas. Our novel findings show that BAI1 expression is significantly reduced in human medulloblastoma (MB) by epigenetic mechanisms, leading us to hypothesize that loss of expression of BAI1 may favor tumor development during cerebellar development. To test this hypothesis, we generated a Bai1 knockout (KO) mouse and detected aberrant activation of Sonic hedgehog signaling and a thicker external granular layer during early postnatal cerebellum development. Furthermore, upon crossing the Bai1 KO mice with mice heterozygous for patched 1 (ptc1 + /-), we found that deficiency of Bai1 dramatically accelerated MB tumorigenesis, the first demonstration that a reduction in Bai1 dosage can promote MB formation in vivo. Moreover, restoration of BAI1 expression in human MB cells inhibited cell growth both in vitro and in vivo. These results support that BAI1 is a novel tumor suppressor for MB and that down-regulation of BAI1 in the cerebellum may drive inappropriate downstream growth signaling and contribute to neoplastic transformation leading to the formation of MB. To further elucidate the molecular mechanisms, we are currently exploring the Bai1 downstream signaling involved in MB tumorigenesis and will present the related findings. Our results also suggest that restoration of BAI1 expression may represent a novel therapeutic intervention for MB. Specifically, we demonstrate that small molecule epigenetic inhibitors of either EZH2 or MBD2 can reactivate BAI1 expression. Taken together, our novel findings provide insight into the neurobiological mechanisms underlying MB tumorigenesis and provide the rationale for the use of epigenetic therapeutics against MB.