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
  • 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.
Products