gsk343 and Brain-Neoplasms

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

Topics: Animals; Benzamides; Biphenyl Compounds; Brain Neoplasms; Brain Stem Neoplasms; Cell Line, Tumor; Cell Proliferation; Chromatin Immunoprecipitation; Chromatography, Liquid; CRISPR-Cas Systems; Cyclin-Dependent Kinase Inhibitor p16; Disease Models, Animal; Enhancer of Zeste Homolog 2 Protein; Gene Knockout Techniques; Glioblastoma; Glioma; Histones; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Indazoles; Mice; Mice, SCID; Molecular Targeted Therapy; Morpholines; Mutation; Neoplasm Transplantation; Neural Stem Cells; Polycomb Repressive Complex 2; Pyridones; Tandem Mass Spectrometry; Tumor Suppressor Protein p14ARF