EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas

Abstract

Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumor that is located in the pons and primarily affects children. Nearly 80% of DIPGs harbor mutations in histone H3 genes, wherein lysine 27 is substituted with methionine (H3K27M). H3K27M has been shown to inhibit polycomb repressive complex 2 (PRC2), a multiprotein complex responsible for the methylation of H3 at lysine 27 (H3K27me), by binding to its catalytic subunit EZH2. Although DIPGs with the H3K27M mutation show global loss of H3K27me3, several genes retain H3K27me3. Here we describe a mouse model of DIPG in which H3K27M potentiates tumorigenesis. Using this model and primary patient-derived DIPG cell lines, we show that H3K27M-expressing tumors require PRC2 for proliferation. Furthermore, we demonstrate that small-molecule EZH2 inhibitors abolish tumor cell growth through a mechanism that is dependent on the induction of the tumor-suppressor protein p16. Genome-wide enrichment analyses show that the genes that retain H3K27me3 in H3K27M cells are strong polycomb targets. Furthermore, we find a highly significant overlap between genes that retain H3K27me3 in the DIPG mouse model and in human primary DIPGs expressing H3K27M. Taken together, these results show that residual PRC2 activity is required for the proliferation of H3K27M-expressing DIPGs, and that inhibition of EZH2 is a potential therapeutic strategy for the treatment of these tumors.

Immunostaining of Increased Expression of Enhancer of Zeste Homolog 2 (EZH2) in Diffuse Midline Glioma H3K27M-Mutant Patients with Poor Survival

“…In diffuse midline glioma, the upregulation of transcription activity is also related to the loss of PRC2 repression function [15, 29]. As indicated by Mohammad et al [40] and Piunti et al [41], H3K27M tumor also requires PRC2-EZH2 for tumor growth preservation and proliferation [40-42]. …”

“…Subsequently, H3K27M progresses through H3K27 acetylation and represses PRC2 activity [41, 42]. Mohammad et al [40] added the evidence that H3K27M is excluded from some loci due to DNA methylation [42]. This methylation results in the incorporation of H3K27M at the weak polycomb target, but this is not enough to reduce the overall activity of PRC2.…”

EZH2 Palmitoylation Mediated by ZDHHC5 in p53-Mutant Glioma Drives Malignant Development and Progression

“…Given its role as a methyltransferase that targets H3K27, EZH2 is considered as a repressor of tumor suppressors such as p19, B-cell lymphoma-2-interacting protein, p57, E-cadherin, and Runt-related transcription factor 3 (38). Recent proteomic and biochemical studies have reported that EZH2 phosphorylation at S21 inhibits H3K27 trimethylation and consequently, expression of polycomb repressive complex 2 target genes (39).…”

Repression of PDK1- and LncRNA HOTAIR-Mediated EZH2 Gene Expression Contributes to the Enhancement of Atractylenolide 1 and Erlotinib in the Inhibition of Human Lung Cancer Cells

“…Increasing evidence indicated that elevated expression of EZH2 was observed in many malignant tumors and was significantly associated with poor outcome in cancer patients [21]. Thus, pharmacological inhibition of EZH2 or agents triggering EZH2 degradation are promising therapeutic strategies for the treatment of various cancer types [22][23][24]. In studies that assess the relationship between EZH2 expression and the clinical outcomes in patients with colorectal cancer treated with anti-EGFR therapeutics, the authors showed that EZH2 expression was associated with the survival in patients with colorectal cancer who were treated with anti-EGFR therapeutics.…”