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

Publication date: 11 June 2018Source: Cancer Cell, Volume 33, Issue 6Author(s): 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 MeirSummaryAdhesion 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.Graphical Abstract

Source: Cancer Cell - July 10, 2018 Category: Cancer & Oncology Source Type: research