Abstract 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 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.
Berry et al. (Thu,) studied this question.