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therapeutic development; therapeutic target; tool; transcriptome sequencing; tumor; tumor growth; tumorigenesis; unpublished works; yeast genetics

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/文摘