Epigenetic Buffering of Proteotoxic Stress Enables Meningioma Cell Survival

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. Here we show that 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 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. Thus, EHMT2/SirT1/HSF1-dependent mitigation of proteotoxic stress represents a promising therapeutic target in meningioma.