The role of novel oncogenic histone H3 lysine variants in defining a therapeutically actionable epigenetic signature

新型致癌组蛋白 H3 赖氨酸变体在定义治疗上可行的表观遗传特征中的作用

• 批准号: 10290714
• 负责人: ANITA H. CORBETT
• 金额: $ 17.86万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10290714
• 关键词: 3-Dimensional; ACVRL1 gene; Acetylation; Address; Affect; Amino Acid Substitution; Amino Acids; Biological Assay; Breast; Breast Cancer cell line; Cancer Etiology; Cell Culture Techniques; Cell Line; Cell Nucleus; Cell Proliferation; Cells; Cessation of life; Chromatin; Chromatin Remodeling Factor; DNA; DNA Sequence Alteration; Detection; Diagnosis; Diagnostic; Dopamine D2 Receptor; ENG gene; Environment; Epigenetic Process; Evolution; Gene Expression; Genes; Genetic Materials; Genetic Transcription; Glioma; Goals; Growth; Histone H3; Histones; Human; In Vitro; Individual; Knowledge; Link; Lysine; Malignant Neoplasms; Mammalian Cell; Methylation; Modeling; Mus; Mutation; N-terminal; Nucleosomes; Oncogenic; Patient-Focused Outcomes; Patients; Phenotype; Positioning Attribute; Post-Translational Protein Processing; Property; Proteins; Reagent; Research; Resources; Role; Saccharomyces cerevisiae; Saccharomycetales; Series; Structural Models; Structure; Surface; System; T47D; Tail; Testing; Therapeutic; Transcriptional Regulation; Variant; Xenograft procedure; Yeasts; cancer diagnosis; cancer therapy; cancer type; cell growth; druggable target; epigenome; epigenomics; experimental study; histone methylation; improved; in silico; inhibitor/antagonist; insight; novel; oncohistone; overexpression; preclinical study; programs; protein H(3); research clinical testing; therapeutic candidate; therapeutic development; therapeutic target; tool; transcriptome sequencing; tumor; tumor growth; tumorigenesis; unpublished works; yeast genetics

PROJECT SUMMARY/ABSTRACT Over 1.7 million individuals will be diagnosed with cancer and 600,000 cancer-associated deaths will occur in the US in 2020. Devoting resources to develop tools and reagents to define mechanisms of oncogenicity and applying this knowledge to the development of therapeutic agents and diagnostic tools is clearly required to improve patient outcome. Recent research has identified cancer-associated amino acid substitutions that occur in the evolutionarily conserved histone proteins, leading to the term “oncohistones.” Examples of such changes linked to cancer include H3K27M, H3G34V/R/D, and H3K36M. While the mechanism of oncogenicity for these mutations varies, each amino acid change perturbs the histone methylation landscape, affecting transcriptional regulation. Understanding how oncohistones alter gene expression can provide critical therapeutic insight. Changes to the histone methylation landscape in H3K27M-expressing gliomas result in dopamine receptor D2 (DRD2) overexpression and these tumors respond to the DRD2 and/or CLPP antagonist ONC201. This example highlights how cancer-associated epigenetic changes can unmask potentially druggable targets. In our preliminary studies, we have identified a series of dominant H3 mutations, termed X to K (R42K, E50K, Q68K, E73K), in which the wildtype amino acid is changed to a lysine, in more than 30 patient tumors in breast and other cancers. Preliminary in vitro experiments suggest that X to K mutation promotes transformation; a major indicator that H3 X to K mutations produce bona-fide oncohistones. However, both how these X to K amino acid changes alter the function of these histones and the mechanism(s) by which X to K oncohistones produce oncogenic phenotypes is unclear. We hypothesize that H3 X to K changes confer oncogenic properties by (1) introducing localized structural changes that alter nucleosome integrity and/or function and/or (2) introducing a new substrate for chromatin modifiers, thereby supporting a novel, and potentially targetable, gene expression program. Drawing on the integrated environment at Emory/Winship, we propose a collaborative multi-PI approach to test our hypothesis through the following aims: Aim 1) Examine the impact of H3 X to K amino acid changes on histone function together with cell and tumor growth; and Aim 2) Define how X to K amino acid changes in histones alter gene expression. Importantly, the proposed studies lay the groundwork for defining both new cancer signatures and druggable targets. Our interdisciplinary team is uniquely qualified to perform the proposed preclinical studies, which are directly related to advancements in cancer treatment and diagnosis. The long-term goal of our studies is to develop diagnostic tools for the detection of oncohistone-associated tumors and identify a therapeutically actionable epigenetic signature in patient tumors characterized by these H3 X to K oncogenic mutations.

项目摘要/摘要 将有超过170万人被诊断出患有癌症，并将发生60万人 在2020年美国，投入资源来开发工具和试剂，以定义致癌性和 显然，将此知识应用于热代理和诊断工具的开发和诊断工具。 改善患者的结果。最近的研究已经确定了与癌症相关的氨基酸取代 在进化中构成组蛋白蛋白，导致术语“ OnCohortones”。这种变化的例子 与癌症有关的，包括H3K27M，H3G34V/R/D和H3K36M。而这些机制的机制 突变变化，每种氨基酸变化都会散布组蛋白甲基化景观，影响转录 规定。了解酒精酮如何改变基因表达可以提供关键的治疗见解。 H3K27M表达神经胶质瘤中组蛋白甲基化景观的变化导致多巴胺受体D2 （DRD2）过表达和这些肿瘤对DRD2和/或CLPP拮抗剂的反应。这个示例 强调了癌症相关的表观遗传变化如何揭示潜在的可药物靶标。 在我们的初步研究中，我们确定了一系列主要的H3突变，称为x至k（r42k，， E50K，Q68K，E73K），其中野生型氨基酸更改为赖氨酸，在30多个患者肿瘤中 乳房和其他癌症。初步的体外实验表明X到K突变促进了转化。 H3 X到K突变的主要指标可在酒精酮上产生诚意。但是，这些X如何到K 氨基酸的变化改变了这些组蛋白的功能和x上x上x的机制 产生致癌表型尚不清楚。我们假设H3 X到K变化会议致癌 通过（1）引入局部结构变化，以改变核小体完整性和/或功能 和/或（2）引入染色质修饰剂的新底物，从而支持小说和 潜在目标，基因表达程序。利用Emory/Winship的综合环境， 我们提出了一种协作的多PI方法，以通过以下目的来检验我们的假设：目标1）检查 H3 X对kamino酸的影响随细胞和肿瘤生长而变化对组蛋白功能。和目标2） 定义X到kamino -to组蛋白的变化如何改变基因表达。重要的是，拟议的研究是 定义新的癌症特征和可药物靶标的基础。我们的跨学科团队是 具有独特的有资格进行拟议的临床前研究，这与进步直接相关 癌症治疗和诊断。我们研究的长期目标是开发检测诊断工具 与酒精酮相关的肿瘤的肿瘤，并鉴定出患者肿瘤的治疗性表观遗传学特征 以这些H3 X为特征到K致癌突变。