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Role of UBR7, a novel H2BK120 E3 ubiquitin ligase, in suppression of breast cancer

UBR7（一种新型 H2BK120 E3 泛素连接酶）在抑制乳腺癌中的作用

基本信息

批准号：
10371220
负责人：
Kunal Rai
金额：
$ 36.32万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10371220
关键词：
Alleles BRCA1 gene Behavior Binding Sites Biological Breast Breast cancer metastasis CDH13 gene Cadherins Cell Adhesion Cell Line Cell physiology Cells ChIP-seq Chromatin Clustered Regularly Interspaced Short Palindromic Repeats DNA Methylation Data Dependence Development Disease Ectopic Expression Enzymes Epigenetic Process Epithelial Gene Expression Genes Genetic Genetic Transcription Genetically Engineered Mouse Guide RNA Histone H2B Histones In Vitro Investigation Kinetics Length Light Lysine MCF10A cells Malignant Neoplasms Mediating Mesenchymal Methyltransferase Modeling Molecular Molecular Mechanisms of Action Molecular Profiling Monoubiquitination Nature Neoplasm Metastasis PHD Finger Pathway interactions Pattern Pharmacologic Substance Pharmacology Phenotype Population Process Proteins Public Health Regulation Research Design Role Series Therapeutic Therapeutic Intervention Tumor Suppressor Proteins Tumor-Derived Work aggressive breast cancer cancer subtypes chromatin modification conditional knockout epigenome epigenomics epithelial to mesenchymal transition experimental study genome-wide human model inhibitor insight knock-down malignant breast neoplasm mammary epithelium molecular phenotype molecular subtypes mouse model new therapeutic target novel novel therapeutic intervention single-cell RNA sequencing targeted treatment transcriptome sequencing treatment strategy triple-negative invasive breast carcinoma tumor tumor growth tumor progression ubiquitin ligase ubiquitin-protein ligase

项目摘要

ABSTRACT Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype with no targeted treatment available. Although we have made tremendous progress in regards to the genetic drivers of this disease, we have limited understanding of the epigenomic alterations that drive specific molecular subtypes of breast cancers. The epigenome consists of an array of chromatin modifications, which collectively form a dynamic chromatin state that impinges upon gene expression networks critical for maintaining cellular identity. Therefore, specific epigenomic alterations may act as drivers of different molecular phenotypes, however we have limited understanding of how specific chromatin patterns may be associated with specific molecular signatures such as basal-like breast cancer. Since epigenetic enzymes are targetable and epigenetic processes are reversible in nature, they could prove to be excellent targets for novel therapeutic strategies against specific molecular phenotypes. Our preliminary data suggests tumor suppressor activities for UBR7, a novel histone modifier, in triple negative breast cancer. We show that UBR7 acts as a E3 ubiquitin ligase for monoubiquitination of histone H2B at K120 residue and may transcriptionally regulate molecular signatures for invasive breast cancers. These data provide rationale for in depth characterization of tumor-suppressor function of UBR7 and identification of therapeutic vulnerabilities imparted by UBR7 loss. Our hypothesis is that UBR7 is a potent tumor suppressor in triple negative breast and promotes invasive behavior in triple- negative breast cancer partly by regulation of cadherin pathway. The objective of this proposal is to first perform in depth characterization of UBR7 tumor-suppressor activity using mouse models, elucidation of downstream cellular processes/pathways and identification of inhibitors/protein targets to inhibit in UBR7-low triple-negative breast cancers. We aim to 1) characterize tumor-suppressor role of UBR7 and determine the genetic context in which UBR7 loss promotes triple-negative breast cancers; 2) determine if UBR7 loss promotes EMT and breast cancer metastasis by alteration of chromatin states and Cadherin genes; and 3) determine genetic and pharmaceutical vulnerabilities of UBR7-deficient triple negative breast cancers. Overall, our studies will provide significant advances in understanding role of epigenome in triple-negative breast cancer tumor progression and define molecular mechanisms underlying contribution of new histone modifier to cancer development.

摘要三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型，无靶向治疗 available.虽然我们在这种疾病的遗传驱动因素方面取得了巨大进展，但我们对驱动乳腺癌特定分子亚型的表观基因组改变的理解有限，癌的表观基因组由一系列染色质修饰组成，它们共同形成一个动态的染色质状态影响对维持细胞身份至关重要的基因表达网络。因此，特定的表观基因组改变可能作为不同分子表型的驱动因素，然而，我们对特定的染色质模式如何与特定的分子生物学特征相关联的理解有限。基底细胞样乳腺癌等特征。由于表观遗传酶具有靶向性和表观遗传性，这些过程在本质上是可逆的，它们可以被证明是新治疗策略的极好靶点。针对特定的分子表型。我们的初步数据表明UBR 7的肿瘤抑制活性，新的组蛋白修饰剂，在三阴性乳腺癌中的应用。我们发现UBR 7作为E3泛素连接酶，组蛋白H2 B在K120残基处的单泛素化，并且可以转录调节以下的分子特征：浸润性乳腺癌这些数据为深入表征肿瘤抑制因子提供了理论基础。 UBR 7的功能和鉴定由UBR 7缺失引起的治疗弱点。我们的假设是 UBR 7在三阴性乳腺中是一种有效的肿瘤抑制因子，并在三阴性乳腺中促进侵袭性行为，阴性乳腺癌部分通过调节钙粘蛋白通路。这项建议的目的是，首先使用小鼠模型深入表征UBR 7肿瘤抑制活性，阐明下游细胞过程/途径和鉴定抑制剂/蛋白靶点以抑制UBR 7-低三阴性乳腺癌我们的目标是：1）描述UBR 7的肿瘤抑制作用，并确定UBR 7在肿瘤发生中的作用。 UBR 7缺失促进三阴性乳腺癌的遗传背景; 2）确定UBR 7缺失是否通过改变染色质状态和钙粘蛋白基因促进EMT和乳腺癌转移;和3）确定UBR 7缺陷型三阴性乳腺癌的遗传和药物脆弱性。总的来说，我们的研究将为理解表观基因组在三阴性乳腺癌中的作用提供重大进展。癌症肿瘤进展，并确定新的组蛋白修饰剂的分子机制，癌症发展