Histone H3.3K27M Represses p16 to Accelerate Gliomagenesis in a Murine Model of DIPG.
Histone H3.3K27M Represses p16 to Accelerate Gliomagenesis in a Murine Model of DIPG.
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DOI：
10.1158/1541-7786.mcr-16-0389
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发表时间：
2017-09
期刊：
影响因子：
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通讯作者：
Becher OJ
中科院分区：
文献类型：
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作者：
Cordero FJ;Huang Z;Grenier C;He X;Hu G;McLendon RE;Murphy SK;Hashizume R;Becher OJ
弥漫性内在脑桥胶质瘤（DIPG）是一种高度侵袭性的儿童脑干肿瘤，与成人GBM在遗传学上的区别在于组蛋白H3变体H3.3（H3 F3 A）中K27 M突变的高患病率。该突变通过抑制H3 K27特异性组蛋白甲基转移酶EZH 2来重编程DIPG的H3 K27 me 3表观遗传景观。这在整体上减少了H3 K27 me 2/3，这是负责细胞命运决定的关键抑制标记，并且还导致H3 K27 me 3在整个表观基因组中的焦点获得。迄今为止，H3.3K27M的肿瘤驱动作用在很大程度上仍然未知。在此，证明了H3.3K27 M与PDGF-B在体内协同作用，增强了胶质瘤的发生并降低了DIPG的p53 WT和敲除鼠模型的存活率。H3.3K27M表达驱动肿瘤源性鼠神经球增殖增加，表明细胞周期失调导致突变型肿瘤恶性程度增加。来自H3.3K27M表达小鼠的肿瘤组织的RNA测序（RNA-Seq）表明PRC 2靶基因的整体上调，以及在发育和细胞增殖的调节剂中富集的新抑制基因的子集。引人注目的是，H3.3K27 M诱导了p16/ink 4a（CDKN 2A）位点的靶向抑制，这是G 0/G1到S相变的关键调节因子。在p16启动子处观察到H3 K27 me 3水平增加;然而，该启动子甲基化的药理学降低并不能拯救p16表达。虽然DNA甲基化也存在于该启动子中，但它不是K27 M依赖性的。有趣的是，DNA甲基化的抑制恢复了p16水平，并且对鼠肿瘤细胞具有细胞毒性。重要的是，这些数据揭示了H3.3K27 M介导的p16抑制是H3.3K27 M肿瘤细胞增殖的重要机制，因为体内cdkn 2a敲除消除了H3.3K27 M和H3.3WT荷瘤小鼠之间的存活差异。
Diffuse Intrinsic Pontine Glioma (DIPG) is a highly aggressive pediatric brainstem tumor genetically distinguished from adult GBM by the high prevalence of the K27M mutation in the histone H3 variant H3.3 (H3F3A). This mutation reprograms the H3K27me3 epigenetic landscape of DIPG by inhibiting the H3K27-specific histone methyltransferase EZH2. This globally reduces H3K27me2/3, critical repressive marks responsible for cell fate decisions, and also causes focal gain of H3K27me3 throughout the epigenome. To date the tumor-driving effects of H3.3K27M remain largely unknown. Here it is demonstrated that H3.3K27M cooperates with PDGF-B in vivo, enhancing gliomagenesis and reducing survival of p53 WT and knockout murine models of DIPG. H3.3K27M expression drives increased proliferation of tumor-derived murine neurospheres, suggesting that cell cycle deregulation contributes to increased malignancy in mutant tumors. RNA sequencing (RNA-Seq) on tumor tissue from H3.3K27M expressing mice indicated global upregulation of PRC2 target genes, and a subset of newly repressed genes enriched in regulators of development and cell proliferation. Strikingly, H3.3K27M induced targeted repression of the p16/ink4a (CDKN2A) locus, a critical regulator of the G0/G1 to S phase transition. Increased levels of H3K27me3 were observed at the p16 promoter; however, pharmacological reduction of methylation at this promoter did not rescue p16 expression. While DNA methylation is also present at this promoter, it is not K27M-dependent. Intriguingly, inhibition of DNA methylation restores p16 levels and is cytotoxic against murine tumor cells. Importantly, these data reveal that H3.3K27M-mediated p16 repression is an important mechanism underlying the proliferation of H3.3K27M tumor cells as in vivo cdkn2a knockout eliminates the survival difference between H3.3K27M and H3.3WT tumor-bearing mice.