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肿瘤组蛋白相互作用组谱分析揭示了高级别神经胶质瘤中不同的致癌机制，并确定了潜在的治疗靶点。

Oncohistone interactome profiling uncovers contrasting oncogenic mechanisms and identifies potential therapeutic targets in high grade glioma.

机构信息

The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, 686 Bay Street, Toronto, ON, M5G 0A4, Canada.

Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada.

出版信息

Acta Neuropathol. 2022 Nov;144(5):1027-1048. doi: 10.1007/s00401-022-02489-2. Epub 2022 Sep 7.

DOI:10.1007/s00401-022-02489-2
PMID:36070144
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9547787/
Abstract

Histone H3 mutations at amino acids 27 (H3K27M) and 34 (H3G34R) are recurrent drivers of pediatric-type high-grade glioma (pHGG). H3K27M mutations lead to global disruption of H3K27me3 through dominant negative PRC2 inhibition, while H3G34R mutations lead to local losses of H3K36me3 through inhibition of SETD2. However, their broader oncogenic mechanisms remain unclear. We characterized the H3.1K27M, H3.3K27M and H3.3G34R interactomes, finding that H3K27M is associated with epigenetic and transcription factor changes; in contrast H3G34R removes a break on cryptic transcription, limits DNA methyltransferase access, and alters mitochondrial metabolism. All 3 mutants had altered interactions with DNA repair proteins and H3K9 methyltransferases. H3K9me3 was reduced in H3K27M-containing nucleosomes, and cis-H3K9 methylation was required for H3K27M to exert its effect on global H3K27me3. H3K9 methyltransferase inhibition was lethal to H3.1K27M, H3.3K27M and H3.3G34R pHGG cells, underscoring the importance of H3K9 methylation for oncohistone-mutant gliomas and suggesting it as an attractive therapeutic target.

摘要

组蛋白 H3 氨基酸 27 位（H3K27M）和 34 位（H3G34R）的突变是儿童型高级别神经胶质瘤（pHGG）的常见驱动因素。H3K27M 突变通过显性负 PRC2 抑制导致 H3K27me3 的全局破坏，而 H3G34R 突变通过抑制 SETD2 导致 H3K36me3 的局部丢失。然而，它们更广泛的致癌机制尚不清楚。我们对 H3.1K27M、H3.3K27M 和 H3.3G34R 互作组进行了表征，发现 H3K27M 与表观遗传和转录因子变化有关；相比之下，H3G34R 消除了隐匿转录的断裂，限制了 DNA 甲基转移酶的进入，并改变了线粒体代谢。所有 3 种突变体与 DNA 修复蛋白和 H3K9 甲基转移酶的相互作用都发生了改变。H3K27M 中包含的核小体中 H3K9me3 减少，并且 cis-H3K9 甲基化对于 H3K27M 发挥其对全局 H3K27me3 的作用是必需的。H3K9 甲基转移酶抑制对 H3.1K27M、H3.3K27M 和 H3.3G34R pHGG 细胞是致命的，这突显了 H3K9 甲基化对于癌组蛋白突变型神经胶质瘤的重要性，并表明其作为一个有吸引力的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43f3/9547787/157e0bf86555/401_2022_2489_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43f3/9547787/0c2009c33d0d/401_2022_2489_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43f3/9547787/c96bff831270/401_2022_2489_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43f3/9547787/51b00426f7ef/401_2022_2489_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43f3/9547787/b0575dac9670/401_2022_2489_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43f3/9547787/c75d9b44d44d/401_2022_2489_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43f3/9547787/157e0bf86555/401_2022_2489_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43f3/9547787/0c2009c33d0d/401_2022_2489_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43f3/9547787/c96bff831270/401_2022_2489_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43f3/9547787/51b00426f7ef/401_2022_2489_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43f3/9547787/b0575dac9670/401_2022_2489_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43f3/9547787/c75d9b44d44d/401_2022_2489_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43f3/9547787/157e0bf86555/401_2022_2489_Fig6_HTML.jpg

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