PDTM-27. EPIGENETIC LOSS OF BAI1 EXPRESSION IN CEREBELLAR GRANULE NEURON PRECURSORS INACTIVATES THE p53 TUMOR SUPPRESSOR AND FACILITATES MEDULLOBLASTOMA FORMATION IN THE CEREBELLUM. (5th November 2018)

• Record Type: Journal Article
• Authors: Zhu, Dan; Osuka, Satoru; Zhang, Zhaobin; Reichert, Zachery; Kanemura, Yonehiro; Nishikawa, Ryo; G. Nelson, William; J. Olson, Jeffrey; Van Meir, Erwin G
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 6
• Page Start: vi209
• Page End: vi209
• Publication Date: 2018-11-05
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy148.868
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Adhesion G-protein coupled receptors (ADGRs) are transmembrane proteins involved in cell-cell/matrix interactions. We show ADGRB1 gene, which encodes Brain-specific angiogenesis inhibitor 1 (BAI1), is epigenetically silenced in human medulloblastomas through a methyl-CpG binding protein 2 (MBD2)-dependent mechanism. Knockout of Adgrb1 in mice augments proliferation of cerebellar granule neuron precursors (GNPs), and increases medulloblastoma penetrance and accelerated death in Ptch1 +/ - mice. BAI1 prevents Mdm2-mediated p53 polyubiquitination, and its loss substantially reduces p53 levels. Reactivation of BAI1/p53 signaling axis by targeting MBD2 pathway suppresses human medulloblastoma growth in orthotopic xenograft models. Our findings highlight the importance of BAI1 loss in medulloblastoma and demonstrate that epigenetic restoration of its expression with a new brain-permeable MBD2 inhibitor has therapeutic potential. Revealing BAI1 as a physiological tumor suppressor in medulloblastoma unveils a direct crosstalk between ADGRs and p53 signaling, and provides a causal relationship between ADGRs and cancer. The discovery of a novel upstream regulator of the p53 tumor suppressor is highly significant because of this pathway's involvement in many cancers. Disruption of the BAI1/mdm2/p53 signaling axis through BAI1 silencing reveals a vulnerability in cancer, and offers an opportunity for therapeutic exploitation through epigenetic reactivation. We provide proof-of-principle that this can be achieved with a chemical scaffold targeting MBD2, and this lead molecule is actionable for translation into a first-in-class therapeutic intervention against medulloblastoma, and possibly other cancers (Zhu D et al, Cancer Cell, in press).