BAI1 Stabilizes p53 to Suppress Medulloblastoma Tumorigenesis

The BAI proteins (BAI1–3) are adhesion G protein-coupled receptors that are predominantly expressed in the brain, and overexpression of the cleavable N-terminus inhibits angiogenesis and glioma growth. Further, ADGRB1–3 (which encode BAI1–3) mutation or silencing has been observed in a variety of tumor types. Zhu and colleagues sought to determine the role of BAI1 in medulloblastoma, a highly aggressive pediatric brain tumor. ADGRB1 was downregulated in medulloblastoma patient samples and cell lines compared with normal cerebellar tissue, and this reduced expression was associated with hypermethylation of the CpG island in the ADGRB1 promoter. SHH-subtype medulloblastoma arises from granule neuron precursors in the developing cerebellum, and deletion of Adgrb1 resulted in aberrant proliferation in the external granular layer. Ptch1 haplodeficiency induces medulloblastoma that resembles human tumors, but additional genetic events are required for increased penetrance and accelerated tumor growth. Deletion of Adgrb1 in Ptch1^+/- transgenic mice accelerated medulloblastoma tumorigenesis and resulted in reduced expression of p53. Mechanistically, BAI1 interacted with MDM2, an E3 ubiquitin ligase that regulates p53 stability, thereby sequestering MDM2 outside of the nucleus, preventing MDM2-mediated polyubiquitination and degradation of p53, and stabilizing p53. In medulloblastoma cells, ADGRB1 silencing was associated with binding of the methyl-CpG binding protein MBD2 to the promoter CpG island, suggesting MBD2 as a potential therapeutic target to reactivate ADGRB1. Indeed, KCC-07, a first-in-class small molecule that blocks MBD2 binding to methylated DNA, reduced binding of MBD2 to the ADGRB1 promoter and restored ADGRB1 expression. Further, KCC-07 suppressed the growth of medulloblastoma cells in vitro, and its systemic delivery suppressed tumor growth and extended survival in two orthotopic medulloblastoma xenograft mouse models. In addition to elucidating a tumor-suppressive role for BAI1 in medulloblastoma through prevention of p53 degradation, these findings demonstrate the potential for therapeutic targeting of MBD2 to promote epigenetic reactivation of ADGRB1.

Zhu D, Osuka S, Zhang Z, Reichert ZR, Yang L, Kanemura Y, et al. BAI1 suppresses medulloblastoma formation by protecting p53 from Mdm2-mediated degradation. Cancer Cell 2018;33:1004–16.

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