Histone H3E50K remodels chromatin to confer oncogenic activity and support an EMT phenotype.

IF 3.4 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
NAR cancer Pub Date : 2025-02-03 eCollection Date: 2025-03-01 DOI:10.1093/narcan/zcaf002
Kirti Sad, Dorelle V Fawwal, Celina Y Jones, Emily J Hill, Katie T Skinner, Miranda L Adams, Severin Lustenberger, Richard S Lee, Sandhya V Lohano, Satvik R Elayavalli, Jonathan Farhi, Christina C Mehta, Laramie D Lemon, Milo B Fasken, Andrew L Hong, Steven A Sloan, Anita H Corbett, Jennifer M Spangle
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引用次数: 0

Abstract

Sequencing of human patient tumors has identified recurrent missense mutations in genes encoding core histones. We report that mutations that convert histone H3 amino acid 50 from a glutamate to a lysine (H3E50K) support an oncogenic phenotype. Expression of H3E50K is sufficient to transform human cells as evidenced by an increase in cell migration and invasion, and an increase in proliferation and clonogenicity. H3E50K also increases the invasive phenotype in the context of co-occurring BRAF mutations, which are present in patient tumors characterized by H3E50K. H3E50 lies on the globular domain surface in a region that contacts H4 within the nucleosome. We find that H3E50K selectively increases chromatin accessibility and perturbs proximal H3 post-translational modifications including H3K27me3; together these changes to chromatin dynamics dysregulate gene expression to support the epithelial-to-mesenchymal transition. Functional studies using Saccharomyces cerevisiae reveal that, while yeast cells that express H3E50K as the sole copy of histone H3 show sensitivity to cellular stressors, including caffeine, H3E50K cells display some genetic interactions that are distinct from the characterized H3K36M oncohistone yeast model. Taken together, these data suggest that additional H3 mutations have the potential to support oncogenic activity and function through distinct mechanisms that dysregulate gene expression.

组蛋白H3E50K重塑染色质,赋予致癌活性并支持EMT表型。
人类肿瘤患者的测序已经确定了编码核心组蛋白的基因的复发性错义突变。我们报道,将组蛋白H3氨基酸50从谷氨酸转化为赖氨酸(H3E50K)的突变支持致癌表型。H3E50K的表达足以转化人细胞,表现为细胞迁移和侵袭增加,增殖和克隆原性增加。H3E50K在BRAF突变共存的情况下也增加了侵袭性表型,这些突变存在于以H3E50K为特征的患者肿瘤中。H3E50位于核小体内与H4接触区域的球状结构域表面。我们发现H3E50K选择性地增加染色质可及性,并干扰近端H3翻译后修饰,包括H3K27me3;这些染色质动力学的变化共同失调基因表达,以支持上皮细胞到间质细胞的转变。利用酿酒酵母进行的功能研究表明,虽然表达H3E50K作为组蛋白H3唯一拷贝的酵母细胞对包括咖啡因在内的细胞应激源敏感,但H3E50K细胞表现出一些与H3K36M组蛋白酵母模型不同的遗传相互作用。综上所述,这些数据表明,额外的H3突变有可能通过不同的机制来支持致癌活性和功能,从而失调基因表达。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
6.90
自引率
0.00%
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0
审稿时长
13 weeks
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