Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas.
Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas.
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DOI：
10.1038/nm.4296
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发表时间：
2017-04
期刊：
影响因子：
82.9
通讯作者：
Shilatifard A
中科院分区：
文献类型：
--
作者：
Piunti A;Hashizume R;Morgan MA;Bartom ET;Horbinski CM;Marshall SA;Rendleman EJ;Ma Q;Takahashi YH;Woodfin AR;Misharin AV;Abshiru NA;Lulla RR;Saratsis AM;Kelleher NL;James CD;Shilatifard A
弥漫性脑桥内神经胶质瘤是一种高度侵袭性的儿童脑干肿瘤，其特点是患者死亡迅速且一致。组蛋白H3的杂合点突变发生在超过80%的这些肿瘤中，并导致赖氨酸到甲硫氨酸的取代（H3 K27 M）。这种组蛋白突变体的表达伴随着多梳抑制复合物2（PRC 2）介导的H3 K27三甲基化（H3 K27 me 3）水平的降低，这被假设为DIPG肿瘤发生的驱动事件。尽管H3 K27 me 3的主要损失，但在H3 K27 M阳性的DIPG细胞中仍然检测到PRC 2活性。为了研究H3 K27 M和PRC 2在DIPG发病机制中的功能作用，我们分析了H3 K27 M突变型DIPG细胞的表观基因组，发现H3 K27 M与增加的H3 K27乙酰化（H3 K27 ac）相关。根据先前的生物化学数据，大多数异型H3 K27 M-K27 ac核小体与活跃转录基因的基因座处的布罗莫结构域蛋白共定位，而PRC 2被排除在这些区域之外;这表明H3 K27 M不在染色质上螯合PRC 2。残留的PRC 2活性需要通过抑制神经元分化和功能来维持DIPG增殖潜力。最后，为了检查阻断DIPG细胞中异型H3 K27 M-K27 ac核小体募集溴结构域蛋白的治疗潜力，我们用BET溴结构域抑制剂进行了体内治疗，并证明它们有效地抑制肿瘤进展，从而将这类化合物鉴定为DIPG中的潜在治疗剂。
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 treatmentsin vivowith BET bromodomain inhibitors and demonstrate that they efficiently inhibit tumor progression, thus identifying this class of compounds as potential therapeutics in DIPG.
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影响因子：
16.6
作者：
Justin N;Zhang Y;Tarricone C;Martin SR;Chen S;Underwood E;De Marco V;Haire LF;Walker PA;Reinberg D;Wilson JR;Gamblin SJ
通讯作者：
Gamblin SJ
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA
影响因子：
64.5
作者：
Chen FX;Woodfin AR;Gardini A;Rickels RA;Marshall SA;Smith ER;Shiekhattar R;Shilatifard A
通讯作者：
Shilatifard A
影响因子：
14.8
作者：
Lee, Tong Ihn;Johnstone, Sarah E.;Young, Richard A.
通讯作者：
Young, Richard A.