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

项目概要 葡萄膜黑色素瘤 (UM) 是一种高度侵袭性的眼癌，导致多达一半的人转移性死亡 患者。根据临床验证的基因表达谱，UM 可分为两个预后组 (GEP)，1 类 GEP 与良好预后相关，2 类 GEP 与不良预后相关。每个 肿瘤类别与特定的驱动突变相关，其中一些突变是我们实验室发现的。在 特别是，高度转移的 2 类肿瘤与肿瘤的失活突变有关 抑制器 BAP1。然而，我们对 BAP1 突变如何导致转移性的了解存在重大差距。 死亡，这阻碍了靶向精准治疗的发展。为了解决这个不足，我的 目标是识别和表征与 BAP1 相互作用的蛋白质。在初步研究中，我进行了 称为 BioID2 的生物素标记质谱技术，并将 HDAC1 鉴定为一种新型 BAP1 相互作用 蛋白质。因此，我建议研究 HDAC1 在介导 BAP1 肿瘤抑制功能中的作用。 我假设 BAP1 通过将 HDAC1 维持在去泛素化状态来调节 HDAC1 的表观遗传功能。 状态。因此，我预测 BAP1 的突变失活会解除 HDAC1 的调节，从而导致 组蛋白乙酰化和促进肿瘤进展的基因表达。我将用以下方法检验这个假设 以下目标：(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 丢失如何通过 HDAC1 催化的组蛋白乙酰化变化来解除转录调控。 我的总体目标是描述 BAP1-HDAC1 相互作用及其破坏的后果 BAP1 突变作为发现新治疗策略的途径。

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.