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therapeutic development; therapeutic target; tool; transcriptome sequencing; tumor; tumor growth; tumorigenesis; unpublished works; yeast genetics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.

项目总结/摘要 超过170万人将被诊断患有癌症，60万人将死于癌症。 2020年在美国。投入资源开发工具和试剂，以确定致癌机制， 显然需要将这些知识应用于治疗剂和诊断工具的开发， 改善患者预后。最近的研究已经确定了癌症相关的氨基酸替换， 在进化上保守的组蛋白中，导致术语“致癌组蛋白”。这种变化的例子 与癌症相关的基因包括H3 K27 M、H3 G34 V/R/D和H3 K36 M。虽然这些肿瘤的致瘤机制 突变的变化，每个氨基酸的变化扰乱组蛋白甲基化景观，影响转录 调控了解癌组蛋白如何改变基因表达可以提供关键的治疗见解。 表达H3 K27 M的胶质瘤中组蛋白甲基化的变化导致多巴胺受体D2 在一些实施方案中，这些肿瘤抑制DRD 2（DRD 2）过表达，并且这些肿瘤对DRD 2和/或CLPP拮抗剂ONC 201应答。该示例 强调了癌症相关的表观遗传变化如何揭示潜在的药物靶点。 在我们的初步研究中，我们已经鉴定了一系列显性H3突变，称为X至K（R42 K， E50 K、Q68 K、E73 K），其中野生型氨基酸被改变为赖氨酸，在30多例患者肿瘤中 乳腺癌和其他癌症。初步的离体实验表明，X到K突变促进转化; 这是H3 X到K突变产生真正的癌组蛋白的主要指标。然而，这些X到K 氨基酸的改变改变了这些组蛋白的功能，并改变了X至K致癌组蛋白的作用机制。 产生致癌表型尚不清楚。我们假设H3 X到K的变化赋予致癌性， 通过（1）引入改变核小体完整性和/或功能的局部结构变化 和/或（2）引入染色质修饰剂的新底物，从而支持新的，和 潜在的靶向基因表达程序。借鉴埃默里/温希普的集成环境， 我们提出了一种协作的多PI方法，通过以下目标来测试我们的假设：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;以及目的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 为定义新的癌症特征和可药物化的目标奠定基础。我们的跨学科团队 唯一有资格进行拟议的临床前研究，这些研究与以下方面的进展直接相关： 癌症治疗和诊断。我们研究的长期目标是开发用于检测的诊断工具 并鉴定患者肿瘤中可治疗的表观遗传标记 以这些H3 X到K致癌突变为特征。