BAI1 Suppresses Medulloblastoma Formation by Protecting p53 from Mdm2-Mediated Degradation

Dan Zhu, Satoru Osuka, Zhaobin Zhang, Zachery R. Reichert, Liquan Yang, Yonehiro Kanemura, Ying Jiang, Shuo You, Hanwen Zhang, Narra S. Devi, Debanjan Bhattacharya, Shingo Takano, G. Yancey Gillespie, Tobey Macdonald, Chalet Tan, Ryo Nishikawa, William G. Nelson, Jeffrey J. Olson, Erwin G. Van Meir

Research output: Contribution to journalArticlepeer-review

Abstract

Adhesion G protein-coupled receptors (ADGRs) encompass 33 human transmembrane proteins with long N termini involved in cell-cell and cell-matrix interactions. We show the ADGRB1 gene, which encodes Brain-specific angiogenesis inhibitor 1 (BAI1), is epigenetically silenced in medulloblastomas (MBs) through a methyl-CpG binding protein MBD2-dependent mechanism. Knockout of Adgrb1 in mice augments proliferation of cerebellar granule neuron precursors, and leads to accelerated tumor growth in the Ptch1 +/− transgenic MB mouse model. BAI1 prevents Mdm2-mediated p53 polyubiquitination, and its loss substantially reduces p53 levels. Reactivation of BAI1/p53 signaling axis by a brain-permeable MBD2 pathway inhibitor suppresses MB growth in vivo. Altogether, our data define BAI1's physiological role in tumorigenesis and directly couple an ADGR to cancer formation. Zhu et al. identify epigenetic silencing of ADGRB1 in medulloblastoma (MB) and show that Adgrb1 loss in a transgenic mouse MB model accelerates tumor growth. ADGRB1 encodes BAI1, which prevents MDM2-mediated p53 polyubiquitination. Rescue of BAI1 expression increases p53 levels and suppresses MB growth.

Original languageEnglish (US)
Pages (from-to)1004-1016.e5
JournalCancer cell
Volume33
Issue number6
DOIs
StatePublished - Jun 11 2018

Keywords

  • ADGRB1
  • BAI1
  • GPCR
  • MBD2
  • Mdm2
  • brain tumor
  • epigenetic silencing
  • medulloblastoma
  • p53

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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