Inhibition of BRG1 suppresses the progression of glioblastoma via repressing oligodendrocyte genes

Abstract

Glioblastoma, the most lethal and pervasive subtype of glioma, has been classified according to both molecular signatures and cell identity. However, the promise of subtype-specific therapy for GBM has yet to be realized. We hypothesize that epigenetic compounds could be effective due to the crucial role of epigenetic regulation in maintaining individual GBM subtypes. We establish a mouse GBM model by expressing AKT3, DN-p53 and PDGFB (ADP) in cortical neural progenitor cells via in utero electroporation. Gene expression analysis demonstrate that ADP glioma exhibits the oligodendrocyte precursor cell (OPC) signature. A small-scale compound screening conducted in cultured ADP tumor cells identify BRM014 (dual ATPase inhibitor of chromatin remodelers BRM/BRG1) as an effective compound. Mechanistically, acute treatment of ADP tumor cells with BRM014 specifically inhibits chromatin accessibility and the expression of oligodendrocyte genes. Importantly, genetic depletion of Brg1 significantly delays tumor progression and prolongs the survival of ADP glioma-bearing mice. Importantly, BRM014 treatment selectively inhibits the growth of human GBM cells with the OPC signature. In sum, our findings demonstrate that the inhibition of ATPase activity of BRG1 is a promising epigenetic therapy for OPC-like GBM.