Epigenetic buffering of proteotoxic stress by EHMT2 enables meningioma growth.

Background: Aggressive meningiomas often display chromosomal abnormalities disrupting more than 20% of the genome, but the mechanisms that allow meningioma cells to thrive nevertheless are unknown. Methods: This study used orthogonal small-molecule screens, gene expression analyses, DNA-binding analyses, epigenetic histone mark datasets, and orthotopic animal models to identify pathways essential for meningioma cell survival. Results: Epigenetic buffering of proteotoxic stress by euchromatic histone methyltransferase 2 (EHMT2) enables meningioma cell survival. A high-throughput small-molecule screen and orthogonal gene expression analysis identified EHMT2 as important for meningioma growth. EHMT2 preferentially binds cis-regulatory elements affecting genes involved in protein processing in the endoplasmic reticulum (ER) in meningioma cells, and EHMT2 inhibition activates the ER stress apoptotic pathway. EHMT2 inhibition also decreases Sirtuin 1 (SirT1)-mediated activation of heat shock factor 1 (HSF1) transcriptional activity, thereby causing collapse of heat shock protein expression. The molecular chaperone and ER stress inhibitor, 4-phenylbutyric acid, abrogates meningioma cell death occurring after EHMT2 inhibition. Importantly, EHMT2 inhibition decreases meningioma growth in mice. Conclusions: EHMT2/SirT1/HSF1-dependent mitigation of proteotoxic stress represents a promising therapeutic target in meningioma.