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

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Oncohistone interactome profiling uncovers contrasting oncogenic mechanisms and identifies potential therapeutic targets in high grade glioma
Acta Neuropathologica ( IF 9.3 ) Pub Date : 2022-09-07 , DOI: 10.1007/s00401-022-02489-2
Robert Siddaway _{1,

2,

3} , Laura Canty _{1,

2} , Sanja Pajovic _{1,

2} , Scott Milos _{1,

2} , Etienne Coyaud _{4,

5} , Stefanie-Grace Sbergio _{1,

6} , Arun Kumaran Vadivel Anguraj _{1,

2} , Evan Lubanszky _{1,

2,

6} , Hwa Young Yun _{6,

7} , Alessia Portante _{1,

2,

6} , Sheyenne Carette _{1,

2} , Cunjie Zhang ₂ , Michael F Moran _{2,

8} , Brian Raught _{4,

9} , Eric I Campos _{7,

8} , Cynthia Hawkins _{1,

2,

3,

6,

10}

Affiliation

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.
Division of Pathology, Hospital for Sick Children, Toronto, ON, Canada.
Princess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, ON, M5G 1L7, Canada.
Université de Lille, Inserm, CHU Lille, U1192 - Protéomique Réponse Inflammatoire Spectrométrie de Masse - PRISM, 59000, Lille, France.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Genetics & Genome Biology Program, Hospital for Sick Children, 686 Bay Street, Toronto, ON, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
Department of Paediatric Laboratory Medicine, Arthur and Sonia Labatt Brain Tumour Research Centre, University of Toronto, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada.

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.

中文翻译：

癌组蛋白相互作用组分析揭示了不同的致癌机制并确定了高级别胶质瘤的潜在治疗靶点

氨基酸 27 (H3K27M) 和 34 (H3G34R) 的组蛋白 H3 突变是儿科型高级别神经胶质瘤 (pHGG) 的复发驱动因素。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 局部丢失。然而，它们更广泛的致癌机制仍不清楚。我们对 H3.1K27M、H3.3K27M 和 H3.3G34R 相互作用组进行了表征，发现 H3K27M 与表观遗传和转录因子变化相关；相比之下，H3G34R 消除了隐蔽转录的中断，限制了 DNA 甲基转移酶的访问，并改变了线粒体代谢。所有 3 个突变体都改变了与 DNA 修复蛋白和 H3K9 甲基转移酶的相互作用。H3K9me3 在含有 H3K27M 的核小体中减少，H3K27M 需要顺式 H3K9 甲基化才能发挥其对全局 H3K27me3 的作用。H3K9 甲基转移酶抑制对 H3.1K27M、H3.3K27M 和 H3.3G34R pHGG 细胞是致命的，强调了 H3K9 甲基化对癌组蛋白突变神经胶质瘤的重要性，并表明它是一个有吸引力的治疗靶点。

更新日期：2022-09-08

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