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

基本信息

批准号：
10436987
负责人：
ANITA H. CORBETT
金额：
$ 21.05万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10436987
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 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 antagonist cancer diagnosis cancer therapy cancer type cell growth diagnostic tool druggable target epigenome epigenomics experimental study histone methylation improved in silico inhibitor 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candidate therapeutic development therapeutic target tool transcriptome sequencing tumor tumor growth tumorigenesis unpublished works yeast genetics

项目摘要

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.

项目概要/摘要超过 170 万人将被诊断患有癌症，60 万人将发生与癌症相关的死亡 2020 年在美国投入资源开发工具和试剂来定义致癌性和显然需要将这些知识应用于治疗剂和诊断工具的开发最近的研究已经确定了与癌症相关的氨基酸替代。进化上保守的组蛋白，导致了“癌组蛋白”这一术语的出现。与癌症相关的包括H3K27M、H3G34V/R/D和H3K36M，而这些的致癌机制。突变各不相同，每个氨基酸的变化都会扰乱组蛋白甲基化景观，影响转录了解癌组蛋白如何改变基因表达可以提供重要的治疗见解。表达 H3K27M 的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) 过度表达，这些肿瘤对 DRD2 和/或 CLPP 拮抗剂 ONC201 有反应。强调了与癌症相关的表观遗传变化如何揭示潜在的可药物靶点。在我们的初步研究中，我们已经确定了一系列显性 H3 突变，称为 X 到 K（R42K、 E50K、Q68K、E73K），其中野生型氨基酸变为赖氨酸，在 30 多个患者肿瘤中乳腺癌和其他癌症的初步体外实验表明，X 到 K 的突变可促进转化； H3 X 到 K 突变产生真正的癌组蛋白的一个主要指标然而，这些 X 到 K 的突变是如何产生的。氨基酸变化改变这些组蛋白的功能以及 X 到 K 癌组蛋白的机制产生致癌表型尚不清楚，我们勇敢地说 H3 X 到 K 的变化会产生致癌性。通过（1）引入改变核小体完整性和/或功能的局部结构变化来特性和/或 (2) 引入一种新的染色质修饰底物，从而支持一种新颖的、和具有潜在针对性的基因表达计划利用埃默里/温希普的综合环境，我们提出了一种协作式多 PI 方法，通过以下目标来检验我们的假设：目标 1) 检查 H3 X 至 K 氨基酸变化对组蛋白功能以及细胞和肿瘤生长的影响；以及目标 2) 定义组蛋白中 X 到 K 氨基酸的变化如何改变基因表达。重要的是，拟议的研究奠定了这一点。我们的跨学科团队是定义新的癌症特征和药物靶点的基础。唯一有资格进行拟议的临床前研究，这些研究与进展直接相关我们研究的长期目标是开发用于检测的诊断工具。癌组蛋白相关肿瘤的研究并确定患者肿瘤中可治疗的表观遗传特征以这些 H3 X 至 K 致癌突变为特征。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Histone H3 E50K mutation confers oncogenic activity and supports an EMT phenotype.

组蛋白 H3 E50K 突变赋予致癌活性并支持 EMT 表型。

DOI：
发表时间：
2023-10-12
期刊：
影响因子：
0
作者：
Sad, K;Jones, C Y;Adams, M;Lustenberger, S;Lee, R S;Elayavalli, S R;Farhi, J;Lemon, L D;Fasken, M B;Corbett, A H;Spangle, J M
通讯作者：
Spangle, J M