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

项目摘要 葡萄膜黑色素瘤(UM)是一种高度侵袭性的眼癌，可导致多达一半的 病人。根据临床验证的基因表达谱，UM可以分为两个预后组 (GEP)，1级预后好，2级预后差。每个人 肿瘤类别与特定的驱动突变有关，其中几个是在我们实验室发现的。在……里面 特别是，高转移的2类肿瘤与肿瘤中的失活突变有关 抑制子BAP1。然而，在我们对BAP1突变如何导致转移的了解中存在着一个主要的缺口 死亡，这阻碍了有针对性的精确治疗的发展。为了解决这一缺陷，我的 目的是鉴定和鉴定与BAP1相互作用的蛋白质。在初步研究中，我进行了一项 生物素标记质谱学技术BioID2和鉴定HDAC1为新的BAP1相互作用蛋白 蛋白。因此，我建议研究HDAC1在BAP1的肿瘤抑制功能中的作用。 我假设BAP1通过维持HDAC1的去泛素化来调节它的表观遗传功能 州政府。因此，我预测BAP1的突变失活会解除对HDAC1的调控，导致 促进肿瘤进展的组蛋白乙酰化和基因表达。我将用 目的如下：(1)确定BAP1如何与HDAC1相互作用并调节其泛素化状态；以及(2) 确定BAP1缺失如何通过HDAC1催化的组蛋白乙酰化改变来解除转录调控。 我的总体目标是通过以下方式描述BAP1-HDAC1的相互作用及其中断的后果 BAP1突变是发现新的治疗策略的途径。

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.