2. Academic Validation
  3. BAI1 Suppresses Medulloblastoma Formation by Protecting p53 from Mdm2-Mediated Degradation

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

  • Cancer Cell. 2018 Jun 11;33(6):1004-1016.e5. doi: 10.1016/j.ccell.2018.05.006.
Dan Zhu 1,  Satoru Osuka 1,  Zhaobin Zhang 1,  Zachery R Reichert 2,  Liquan Yang 1,  Yonehiro Kanemura 3,  Ying Jiang 4,  Shuo You 1,  Hanwen Zhang 1,  Narra S Devi 1,  Debanjan Bhattacharya 1,  Shingo Takano 5,  G Yancey Gillespie 6,  Tobey Macdonald 7,  Chalet Tan 4,  Ryo Nishikawa 8,  William G Nelson 2,  Jeffrey J Olson 9,  Erwin G Van Meir 10
Affiliations

Affiliations

  • 1 Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, School of Medicine, Emory University, Atlanta, GA 30322, USA; Department of Hematology & Medical Oncology, School of Medicine, Emory University, Atlanta, GA 30322, USA.
  • 2 Johns Hopkins University, 401 North Broadway, Baltimore, MD 21287, USA.
  • 3 Division of Regenerative Medicine, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, 2-1-14 Hoenzaka, Chuo-ku, Osaka 540-0006, Japan.
  • 4 Department of Pharmaceutical Sciences, Mercer University, Atlanta, GA 30322, USA.
  • 5 Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
  • 6 Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • 7 Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University, 1365C Clifton Road N.E, C5078, Atlanta, GA 30322, USA.
  • 8 Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Saitama, Japan.
  • 9 Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, School of Medicine, Emory University, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University, 1365C Clifton Road N.E, C5078, Atlanta, GA 30322, USA; Department of Hematology & Medical Oncology, School of Medicine, Emory University, Atlanta, GA 30322, USA.
  • 10 Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, School of Medicine, Emory University, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University, 1365C Clifton Road N.E, C5078, Atlanta, GA 30322, USA; Department of Hematology & Medical Oncology, School of Medicine, Emory University, Atlanta, GA 30322, USA. Electronic address: [email protected].
PMID: 29894688 DOI: 10.1016/j.ccell.2018.05.006
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.

Keywords

ADGRB1; BAI1; GPCR; MBD2; Mdm2; brain tumor; epigenetic silencing; medulloblastoma; p53.

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