Abstract
Glioblastoma (GBM) is the most common and lethal type of malignant brain tumor in adults. GBM cells are highly invasive and diffusely infiltrate throughout the brain, which strongly restricts multimodal therapies. Acquiring a better knowledge of molecular defects underlying GBM invasion is essential for the development of effective therapies. Brain-specific Angiogenesis Inhibitor 1 (BAI1) is a transmembrane receptor of the adhesion GPCR family widely expressed in normal brain, but its expression is lost in the majority of human brain tumors. We have previously shown that BAI1 is epigenetically silenced in most GBM and restoration of its expression can inhibit glioma growth in vitro and in vivo (Zhu D. et al, Cancer Res, 2012). Recently, we reported that BAI1 protects p53 from Mdm2-mediated degradation and regulate tumor growth in medulloblastoma (Zhu D. et al, Cancer Cell, 2018). However, it is unclear whether BAI1 loss is important for tumor invasion in GBM. We found that restoration of BAI1 expression in GBM cells suppressed mesenchymal transition. Microarray analysis of the TCGA dataset revealed that BAI1 expression inversely correlates with the expression of many key mesenchymal genes, including Fibronectin1, SLUG, and TWIST1. Reduced BAI1 expression also correlates with poor outcome. Restoration of BAI1 expression suppresses mesenchymal gene expression and dramatically decreases GBM cell brain invasion in mice. Mechanistically, the N-terminal thrombospondin type 1 repeat (TSR#1) of BAI1 inhibits the maturation process of TGFβ1, a key growth factor involved in EMT. BAI1 is silenced epigenetically in GBM cells by MBD2, and its expression can be reactivated by KCC-07, a blood-brain barrier permeable MBD2 inhibitor. We found that GBM cells treated by KCC-07 exhibited decreased tumor invasion. These experiments demonstrate that epigenetic silencing of BAI1 is important for activation of the GBM invasive phenotype through TGFβ1 pathway activation. Epigenetic targeting of this process by KCC-07 can reduce GBM invasion.