Epigenetic deregulation and tumor progression due to the loss of a novel interaction between HDAC1 and BAP1 in uveal melanoma

由于葡萄膜黑色素瘤中 HDAC1 和 BAP1 之间新型相互作用的丧失导致表观遗传失调和肿瘤进展

• 批准号: 10238965
• 负责人: Daniel Alexander Rodriguez
• 金额: $ 4.24万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238965
• 关键词: Acetylation; Address; Adult; Algorithms; Automobile Driving; BARD1 gene; BRCA1 gene; Binding; Bioinformatics; Biotin; C-terminal; CRISPR/Cas technology; Catalytic Domain; Cell Line; Cells; Cessation of life; ChIP-seq; Chromatin; Chromosome 3; Chromosome Deletion; Chromosomes; Clinical; Co-Immunoprecipitations; Complex; DNA Repair; Data; Development; Disease; Engineering; Enzymes; Epigenetic Process; Family; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; HDAC1 gene; Histone Acetylation; Histone Deacetylase Inhibitor; Histones; Homeostasis; Knowledge; Label; Laboratories; Lead; Liver; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Mediating; Melanoma Cell; Metastatic to; Modeling; Monosomy; Mutate; Mutation; N-terminal; Neoplasm Metastasis; Nuclear; Pathway interactions; Patients; Play; Post-Translational Protein Processing; Precision therapeutics; Prognosis; Proteins; Recombinants; Regulation; Research; Risk; Role; Severity of illness; Techniques; Testing; Therapeutic Effect; Transcriptional Regulation; Tumor Suppression; Tumor Suppressor Proteins; Ubiquitin; Ubiquitination; Uveal Melanoma; Work; base; driver mutation; experimental study; genomic aberrations; host cell factor C1; insight; knock-down; malignant neoplasm of eye; melanocyte; member; mortality; mutant; novel; novel therapeutic intervention; prognostic; response; transcriptome sequencing; transcriptomics; tumor; tumor progression; ubiquitin C-terminal hydrolase; ubiquitin isopeptidase

Project Summary Uveal melanoma (UM) is a highly aggressive eye cancer that leads to metastatic death in up to half of patients. UM can be divided into two prognostic groups based on a clinically validated gene expression profile (GEP), with class 1 GEP being associated with good prognosis and class 2 GEP with bad prognosis. Each tumor class is associated with specific driver mutations, several of which were discovered in our laboratory. In particular, the highly metastatic Class 2 tumors are associated with inactivating mutations in the tumor suppressor BAP1. However, a major gap exists in our knowledge of how BAP1 mutations lead to metastatic death, which has thwarted the development of targeted precision therapy. To address this deficiency, my objective is to identify and characterize proteins that interact with BAP1. In preliminary studies, I performed a biotin-labeling mass spectrometry technique called BioID2 and identified HDAC1 as a novel BAP1-interacting protein. Thus, I propose to investigate the role of HDAC1 in mediating the tumor suppressor function of BAP1. I hypothesize that BAP1 regulates the epigenetic functions of HDAC1 by maintaining it in a de-ubiquitinated state. Accordingly, I predict that mutational inactivation of BAP1 deregulates HDAC1, leading to changes in histone acetylation and gene expression that promote tumor progression. I will test this hypothesis with the following Aims: (1) Determine how BAP1 interacts with HDAC1 and regulates its ubiquitination state, and (2) Identify how BAP1 loss deregulates transcription through histone acetylation changes catalyzed by HDAC1. My overall objective is to characterize the BAP1-HDAC1 interaction and the consequences of its disruption by BAP1 mutations as an avenue to discovering new therapeutic strategies.

项目摘要 葡萄膜黑色素瘤（UM）是一种高度侵袭性的眼癌， 患者根据临床验证的基因表达谱，UM可分为两个预后组 (GEP)GEP 1级预后好，GEP 2级预后差。每个 肿瘤分类与特定的驱动突变相关，其中几个是在我们的实验室中发现的。在 特别地，高转移性2类肿瘤与肿瘤中的失活突变相关， 抑制因子BAP 1。然而，我们对BAP 1突变如何导致转移性乳腺癌的认识存在很大差距。 死亡，这阻碍了靶向精确治疗的发展。为了弥补这一不足，我 目的是鉴定和表征与BAP 1相互作用的蛋白质。在初步研究中，我进行了 生物素标记质谱技术称为BioID 2，并确定HDAC 1作为一种新的BAP 1相互作用 蛋白因此，我建议研究HDAC 1在介导BAP 1的肿瘤抑制功能中的作用。 我假设BAP 1通过维持HDAC 1在去泛素化的蛋白质中的表达来调节HDAC 1的表观遗传功能。 状态因此，我预测BAP 1的突变失活会使HDAC 1失活，导致HDAC 1的变化。 组蛋白乙酰化和基因表达促进肿瘤进展。我将测试这个假设与 以下目的：（1）确定BAP 1如何与HDAC 1相互作用并调节其泛素化状态，以及（2） 确定BAP 1丢失如何通过HDAC 1催化的组蛋白乙酰化变化来解除转录。 我的总体目标是描述BAP 1-HDAC 1相互作用及其破坏的后果， BAP 1突变是发现新治疗策略的途径。