Overexpression of MBD2 in Glioblastoma Maintains Epigenetic Silencing and Inhibits the Anti-Angiogenic Function of the Tumor Suppressor Gene BAI1

• Type of Material: Article
• Authors: Dan Zhu, Emory University; Stephen B Hunter, Emory University; Paula M Vertino, Emory University; Erwin Van Meir, Emory University
• Language: English
• Date: 2011-09-01
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: ©2011 American Association for Cancer Research.
• Final Published Version (URL): http://cancerres.aacrjournals.org/content/71/17/5859
• Title of Journal or Parent Work: Cancer Research
• ISSN: 0008-5472
• Volume: 71
• Issue: 17
• Start Page: 5859
• End Page: 5870
• Grant/Funding Information: Financial support: NIH R01-CA86335 (EGVM), NIH RO1-CA077337 (PMV), the Southeastern Brain Tumor Foundation (DZ and EGVM) and the University Research Council of Emory University (EGVM).
• Keywords: BAI1; MBD2; overexpression; epigenetic; glioblastoma
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Oncology

Abstract

Brain Angiogenesis Inhibitor 1 (BAI1) is a putative G protein-coupled receptor with potent anti-angiogenic and anti-tumorigenic properties that is mutated in certain cancers. BAI1 is expressed in normal human brain, but it is frequently silenced in glioblastoma multiforme (GBM). In this study we show this silencing event is regulated by overexpression of methyl-CpG-binding domain protein 2 (MBD2), a key mediator of epigenetic gene regulation, which binds to the hypermethylated BAI1 gene promoter. In glioma cells, treatment with the DNA demethylating agent 5-aza-2′-deoxycytidine (5-Aza-dC) was sufficient to reactivate BAI1 expression. Chromatin immunoprecipitation (ChIP) showed that MBD2 was enriched at the promoter of silenced BAI1 in glioma cells and that MBD2 binding was released by 5-Aza-dC treatment. RNAi-mediated knockdown of MBD2 expression led to reactivation of BAI1 gene expression and restoration of BAI1 functional activity, as indicated by increased anti-angiogenic activity in vitro and in vivo. Taken together, our results suggest that MBD2 overexpression during gliomagenesis may drive tumor growth by suppressing the anti-angiogenic activity of a key tumor suppressor. These findings have therapeutic implications since inhibiting MBD2 could offer a strategy to reactivate BAI1 and suppress glioma pathobiology.