Abstract
Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem tumor characterized by rapid and uniform patient demise. A heterozygous point mutation of histone H3 occurs in more than 80% of these tumors and results in a lysine-to-methionine substitution (H3K27M). 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. Despite a major loss of H3K27me3, PRC2 activity is still detected in DIPG cells positive for H3K27M. 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, 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.
Original language | English (US) |
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Pages (from-to) | 493-500 |
Number of pages | 8 |
Journal | Nature Medicine |
Volume | 23 |
Issue number | 4 |
DOIs | |
State | Published - Apr 1 2017 |
Funding
A.P. is supported by a long-term EMBO fellowship (ALTF 372-2015), and his work in the Shilatifard lab is supported by AIRC and Marie Curie Actions-People-COFUND. R.H. is supported by US National Institutes of Health grant RO1NS093079, the Matthew Larson Foundation and the Bear Necessities Pediatric Cancer Foundation and Rally Foundation. Proteomics services were performed by the Northwestern Proteomics Core Facility, generously supported by NCI CCSG P30CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center, and the National Resource for Translational and Developmental Proteomics supported by P41GM108569. Studies in regards to the development of targeted therapeutics for DIPG within our groups are partially supported by the generous support of J. McNicholas Pediatric Brain Tumor Foundation. Studies in the Shilatifard laboratory are supported by NCI grant R35CA197569.
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology