Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas

• Published in: Nature medicine Vol. 23; no. 4; pp. 493 - 500
• Main Authors: Piunti, Andrea, Hashizume, Rintaro, Morgan, Marc A, Bartom, Elizabeth T, Horbinski, Craig M, Marshall, Stacy A, Rendleman, Emily J, Ma, Quanhong, Takahashi, Yoh-hei, Woodfin, Ashley R, Misharin, Alexander V, Abshiru, Nebiyu A, Lulla, Rishi R, Saratsis, Amanda M, Kelleher, Neil L, James, C David, Shilatifard, Ali
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-04-2017; Nature Publishing Group
• Subjects: 45; 45/15; 45/22; 45/91; 631/337/100; 631/67/1922; Acetylation - drug effects; Animals; Antibodies; Azepines - pharmacology; Biomedicine; Brain Stem Neoplasms - genetics; Cancer Research; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Proliferation - genetics; Chromatin - drug effects; Chromatin - metabolism; Epigenomics; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Genomes; Glioma - genetics; Hematology; Histone Code - drug effects; Histone Code - genetics; Histones - drug effects; Histones - genetics; Humans; Infectious Diseases; letter; Medicine; Metabolic Diseases; Methylation - drug effects; Mice; Molecular Medicine; Molecular Targeted Therapy; Mutation; Neurogenesis - drug effects; Neurogenesis - genetics; Neurosciences; Nucleosomes - drug effects; Nucleosomes - metabolism; Oncology; Pediatrics; Polycomb Repressive Complex 2 - drug effects; Polycomb Repressive Complex 2 - metabolism; Protein Transport; Proteins; RNA polymerase; RNA-Binding Proteins - antagonists & inhibitors; RNA-Binding Proteins - metabolism; Triazoles - pharmacology; Xenograft Model Antitumor Assays; United States > US; Illinois; Chicago Illinois
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.4296

Nucleosomes containing mutant K27M histones in diffuse intrinsic pediatric gliomas (DIPG) exclude PRC2 binding and recruit BET bromodomain proteins; however, residual PRC2-dependent repression of specific loci, is required for DIPG oncogenesis. These results provide a rationale for targeting these epigenetic regulators in patients.
Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem tumor characterized by rapid and uniform patient demise
1
. A heterozygous point mutation of histone H3 occurs in more than 80% of these tumors and results in a lysine-to-methionine substitution (H3K27M)
2
,
3
. Expression of this histone mutant is accompanied by a reduction in the levels of polycomb repressive complex 2 (PRC2)-mediated H3K27 trimethylation (H3K27me3), and this is hypothesized to be a driving event of DIPG oncogenesis
4
,
5
. Despite a major loss of H3K27me3, PRC2 activity is still detected in DIPG cells positive for H3K27M
6
,
7
. To investigate the functional roles of H3K27M and PRC2 in DIPG pathogenesis, we profiled the epigenome of H3K27M-mutant DIPG cells and found that H3K27M associates with increased H3K27 acetylation (H3K27ac). In accordance with previous biochemical data
5
, the majority of the heterotypic H3K27M-K27ac nucleosomes colocalize with bromodomain proteins at the loci of actively transcribed genes, whereas PRC2 is excluded from these regions; this suggests that H3K27M does not sequester PRC2 on chromatin. Residual PRC2 activity is required to maintain DIPG proliferative potential, by repressing neuronal differentiation and function. Finally, to examine the therapeutic potential of blocking the recruitment of bromodomain proteins by heterotypic H3K27M-K27ac nucleosomes in DIPG cells, we performed treatments
in vivo
with BET bromodomain inhibitors and demonstrate that they efficiently inhibit tumor progression, thus identifying this class of compounds as potential therapeutics in DIPG.