Epigenetic Enablers of Meningioma Growth

Abstract

Meningiomas are the most common primary intracranial brain tumor, often causing significant disability and sometimes even death. The most aggressive meningiomas commonly exhibit extensive genomic disruption that can lead to genotoxic and proteotoxic stress, but the mechanisms that enable these tumors to thrive are unknown. To date, meningiomas have no effective chemotherapy. This study used a high-throughput bioactive small molecule screen of established meningioma cell lines and RNA-sequencing of patient meningiomas to identify EHMT2/G9a inhibitors as potent cytotoxic agents in meningioma in vitro. Further, studies using the small molecule EHMT2/G9a inhibitor, UNC0631 demonstrated reduced tumor growth in an orthotopic xenograft mouse model of meningioma in vivo. We used CUT&Tag and transcriptomic analyses of established meningioma cell lines after EHMT2/G9a inhibition to identify the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress apoptotic signaling pathway as key factors in EHMT2/G9a-mediated meningioma cell death. After EHMT2/G9a inhibition, we observed a collapse of heat shock protein expression and hypothesized that downregulation of a deacetylase, Sirtuin 1 (SirT1), may be responsible. Consistent with decreased SirT1 activity, Heat Shock Factor 1 exhibited increased lysine acetylation and decreased DNA binding at the promoters of downregulated heat shock proteins. Overexpression of SirT1 or shRNA-mediated knockdown of the ER stress response mediators, ATF4 or CHOP/DDIT3, decreased meningioma cell death caused by EHMT2/G9a inhibition. The molecular chaperone and ER stress inhibitor, 4-phenylbutyric acid, abrogated meningioma cell death occurring after EHMT2/G9a inhibition. In conclusion, epigenetic maintenance of heat shock protein activity and suppression of the UPR/ER stress apoptotic signaling pathway by EHMT2/G9a and SirT1 are essential for aggressive meningioma growth.