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

Thomas K. Sears; Matthew McCord; Wenxia Wang; Alicia Steffens; Kathleen McCortney; Rahul Chaliparambil; Jann N. Sarkaria; Craig M. Horbinski

doi:10.1172/jci.insight.195385

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

Thomas K. Sears,¹ Matthew McCord,² Wenxia Wang,¹ Alicia Steffens,¹ Kathleen McCortney,¹ Rahul Chaliparambil,¹ Jann N. Sarkaria,³ and Craig M. Horbinski⁴

Published October 9, 2025 - More info

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Abstract

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

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

Thomas K. Sears,¹ Matthew McCord,² Wenxia Wang,¹ Alicia Steffens,¹ Kathleen McCortney,¹ Rahul Chaliparambil,¹ Jann N. Sarkaria,³ and Craig M. Horbinski⁴

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

Thomas K. Sears,1 Matthew McCord,2 Wenxia Wang,1 Alicia Steffens,1 Kathleen McCortney,1 Rahul Chaliparambil,1 Jann N. Sarkaria,3 and Craig M. Horbinski4

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Thomas K. Sears,¹ Matthew McCord,² Wenxia Wang,¹ Alicia Steffens,¹ Kathleen McCortney,¹ Rahul Chaliparambil,¹ Jann N. Sarkaria,³ and Craig M. Horbinski⁴