# Methylation-induced suppression of YAP/TAZ confers sensitivity to HDAC inhibitors in high-grade IDH mutant gliomas

## TL;DR

IDH mutant gliomas are more sensitive to HDAC inhibitors because they suppress YAP and TAZ genes.

## Contribution

The study identifies YAP/TAZ suppression as a mechanism for HDAC inhibitor sensitivity in IDHmut gliomas.

## Key findings

- IDHmut gliomas show greater sensitivity to HDACi compared to IDHwt gliomas.
- YAP and TAZ are methylated and suppressed in IDHmut gliomas, contributing to HDACi sensitivity.
- Belinostat improves survival in IDHmut glioma models but not in IDHmut GBM models.

## Abstract

IDH1/2 mutations (IDHmut) increase methylation of DNA and histones in gliomas. IDHmut inhibitors are effective against low-grade IDHmut gliomas, but new strategies against high-grade IDHmut gliomas are needed. Although histone deacetylase inhibitors (HDACi) are ineffective against IDHwt glioblastoma (GBM), their potential in IDHmut gliomas has not been extensively studied. We previously established that IDHmut gliomas are more sensitive to HDACi than IDHwt GBM. Here we show that IDHmut is associated with greater sensitivity to HDACi only in glioma, not in IDHmut chondrosarcoma or cholangiocarcinoma. While HDACi induced more histone acetylation and gene regulation in IDHmut glioma than in IDHwt GBM, such acetylation was mostly within gene deserts, whereas IDHmut glioma promoters paradoxically lost histone acetylation. Two mediators of HDACi resistance, YAP and TAZ, were methylated and suppressed in IDHmut gliomas but not in other IDHmut cancers. Inducing YAP or TAZ expression in IDHmut gliomas conferred resistance to HDACi. Finally, belinostat extended in vivo survival only in IDHmut glioma models, not in IDHmut GBM models. Our findings provide a mechanistic rationale for further studies of HDACi in patients with IDHmut glioma, as well as the potential use of YAP/TAZ as a biomarker of HDACi sensitivity in cancers.

Because IDH mutant gliomas suppress two important genes, YAP and TAZ, they are more sensitive to a class of drugs called HDAC inhibitors.