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

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.

• Authors: 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
• Journal: Cancer cell (Cancer Cell) Vol. 33 Issue 6 Pg. 1004-1016.e5 (06 11 2018) ISSN: 1878-3686 [Electronic] United States
• PMID: 29894688 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

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

Topics

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