MB-05: BAI1 IS A TUMOR SUPPRESSOR IN MEDULLOBLASTOMA

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 (1). We now found that BAI1 expression is downregulated in human medulloblastoma (MB) by epigenetic mechanisms, involving CpG island promoter methylation, methylated DNA binding protein MBD2, and histone-lysine N-methyl transferase EZH2. Restoration of BAI1 expression reduced MB cell proliferation and tumor growth in mice xenografts. Targeting MBD2 and EZH2 with small molecules reactivated BAI1 expression, and suppressed tumor growth, supporting the use of epigenetic therapeutics against MB. To more directly examine whether loss of BAI1 expression may favor tumor development during cerebellar development, we generated a Bai1 knockout (KO) mouse. We detected a thicker external granular layer (EGL) during early postnatal cerebellum development, which was accompanied by increased proliferation in cGNPs and aberrant activation of Sonic hedgehog signaling. Bai1 loss alone was not sufficient to initiate tumor formation, but dramatically accelerated MB tumorigenesis when crossed to mice heterozygous for patched 1 (ptc1^+/-). We will present our latest findings on the signaling pathways underlying BAI1's tumor suppressor activity in the cerebellum. Altogether, our novel findings evidence a physiological function for BAI1 in the brain, as a potent suppressor of cerebellar transformation. References: 1. Zhu D, Hunter SB, Vertino PM, Van Meir EG. Overexpression of MBD2 in glioblastoma maintains epigenetic silencing and inhibits the antiangiogenic function of the tumor suppressor gene BAI1. Cancer Research. 2011;71:5859-5870.