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

• Published in: Nature medicine Vol. 23; no. 4; pp. 483 - 492
• Main Authors: Mohammad, Faizaan, Weissmann, Simon, Leblanc, Benjamin, Pandey, Deo P, Højfeldt, Jonas W, Comet, Itys, Zheng, Chunqin, Johansen, Jens Vilstrup, Rapin, Nicolas, Porse, Bo T, Tvardovskiy, Andrey, Jensen, Ole N, Olaciregui, Nagore G, Lavarino, Cinzia, Suñol, Mariona, de Torres, Carmen, Mora, Jaume, Carcaboso, Angel M, Helin, Kristian
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2017; Nature Publishing Group
• Subjects: 13/100; 14; 38; 38/1; 38/39; 38/91; 631/337/100; 631/67/1922; 692/699/67/1922; 82; 82/80; Animals; Benzamides - pharmacology; Biomedicine; Brain cancer; Brain Neoplasms - genetics; Brain Stem Neoplasms - genetics; Brain tumors; Cancer Research; Cell Line, Tumor; Cell Proliferation - genetics; Chromatin Immunoprecipitation; Chromatography, Liquid; CRISPR-Cas Systems; Cyclin-Dependent Kinase Inhibitor p16 - drug effects; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Disease Models, Animal; Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors; Enhancer of Zeste Homolog 2 Protein - genetics; Gene Knockout Techniques; Glioblastoma - genetics; Glioma - genetics; Histones - genetics; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Indazoles - pharmacology; Infectious Diseases; Medical prognosis; Metabolic Diseases; Mice; Mice, SCID; Molecular Medicine; Molecular Targeted Therapy; Mutation; Neoplasm Transplantation; Neural Stem Cells; Neurosciences; Pediatrics; Polycomb Repressive Complex 2 - genetics; Proteins; Pyridones - pharmacology; Tandem Mass Spectrometry; Tumor Suppressor Protein p14ARF - drug effects; Tumor Suppressor Protein p14ARF - genetics; Tumors; Denmark; Spain
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.4293

Although mutant H3K27M histones inhibit PRC2 in diffuse intrinsic pontine gliomas, these tumors exhibit significant amounts of PRC2 activity. The repression of several genes, including INK4A , by residual EZH2 activity is required for tumor growth, and EZH2 inhibitors therefore represent potential therapies for these patients. 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 INK4A . 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.