# EZH2 overexpression is associated with aggressive behavior and promotes cell proliferation in CNS WHO grade 3 meningiomas

## TL;DR

EZH2 overexpression is linked to aggressive behavior in grade 3 meningiomas and promotes tumor cell proliferation, suggesting it could be a potential therapeutic target.

## Contribution

This study demonstrates the functional relevance of EZH2 in CNS WHO grade 3 meningiomas and shows its inhibition can reduce tumor growth.

## Key findings

- Higher EZH2 levels correlate with shorter survival and increased proliferation in grade 3 meningiomas.
- EZH2 inhibition with EPZ-6438 reduces cell proliferation and tumor growth in vitro and in a mouse model.
- 9p21.3 deletion and H3 K27me3 loss are associated with elevated EZH2 expression.

## Abstract

Central nervous system (CNS) World Health Organization (WHO) grade 3 meningiomas are aggressive tumors of the CNS whose clinical management is particularly challenging due to the lack of effective systemic treatment options. Recent multiomic studies revealed increasing expression and activity of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) in parallel with the increase in meningioma grade. This study primarily aims to characterize in detail the clinical and molecular correlates of EZH2 expression in grade 3 meningiomas and to investigate its functional role both in vitro and in vivo.

EZH2 expression was correlated with clinical outcome data as well as with the loss of p16 and H3 K27me3, 9p21.3 deletion, and pTERT mutational status in a cohort of 49 grade 3 meningiomas. Effects of the EZH2 methyltransferase inhibitor EPZ-6438 were investigated on the IOMM-Lee human grade 3 meningioma cell line.

Higher levels of EZH2 overexpression were associated with shorter overall and local progression-free survival and higher proliferative activity in our grade 3 meningioma cohort. Deletion of the 9p21.3 region and loss of H3 K27me3 were related to higher EZH2 expression, while loss of p16 and pTERT mutations did not show significant correlation. EPZ-6438 treatment exerted concentration-dependent inhibitory effect on IOMM-Lee cell proliferation through inhibition of cell cycle progression, increased p21, and decreased FOXM1 expression. Upon per os EPZ-6438 treatment, a slight inhibition of tumor growth with different underlying mechanisms was detected in a mouse heterotopic xenograft model.

Our findings demonstrate that EZH2 is functionally relevant in grade 3 meningiomas, primarily through promoting cell proliferation.