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

doi:10.1016/j.ccell.2018.05.006

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.

Authors

Dan Zhu¹, Satoru Osuka¹, Zhaobin Zhang¹, Zachery R Reichert², Liquan Yang¹, Yonehiro Kanemura³, Ying Jiang⁴, Shuo You¹, Hanwen Zhang¹, Narra S Devi¹, Debanjan Bhattacharya¹, Shingo Takano⁵, G Yancey Gillespie⁶, Tobey Macdonald⁷, Chalet Tan⁴, Ryo Nishikawa⁸, William G Nelson², Jeffrey J Olson⁹, Erwin G Van Meir¹⁰

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: evanmei@emory.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Angiogenic Proteins / genetics
Angiogenic Proteins / metabolism*
Animals
Cell Line, Tumor
Cerebellar Neoplasms / drug therapy
Cerebellar Neoplasms / genetics
Cerebellar Neoplasms / metabolism*
HCT116 Cells
Humans
Kaplan-Meier Estimate
Medulloblastoma / drug therapy
Medulloblastoma / genetics
Medulloblastoma / metabolism*
Mice, Inbred C57BL
Mice, Knockout
Mice, Nude
Proto-Oncogene Proteins c-mdm2 / genetics
Proto-Oncogene Proteins c-mdm2 / metabolism*
RNA Interference
Receptors, G-Protein-Coupled
Small Molecule Libraries / pharmacology
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism*
Xenograft Model Antitumor Assays

Substances

ADGRB1 protein, human
Angiogenic Proteins
Receptors, G-Protein-Coupled
Small Molecule Libraries
Tumor Suppressor Protein p53
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2

Abstract

Publication types

MeSH terms

Substances

Grants and funding