The Role of the Epigenetic Regulator UHRF1 in Colon Tumorigenesis

表观遗传调节因子 UHRF1 在结肠肿瘤发生中的作用

基本信息

批准号：
9763321
负责人：
Alison Ann Lanctot Chomiak
金额：
$ 6.27万
依托单位：
VAN ANDEL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9763321
关键词：
3-Dimensional Aberrant DNA Methylation Acute Address Architecture Azacitidine Biological Models Candidate Disease Gene Career Transition Award Cause of Death Cell Line Cells Chromatin Colon Carcinoma Colonic Neoplasms Colorectal Cancer Colorectal Neoplasms CpG Island Methylator Phenotype CpG Islands DNA DNA Damage DNA Maintenance DNA Methylation DNA Methyltransferase Inhibitor DNA Modification Methylases Data Diagnosis Disease Dose Elements Epigenetic Process Exhibits Faculty Foundations Frequencies Gene Expression Gene Silencing Gene Targeting Genetic Genomics Goals Growth Heterogeneity Human Hypermethylation Intestinal Neoplasms Intestines Large Intestine Carcinoma Maintenance Malignant - descriptor Malignant Neoplasms Mediating Methods Microsatellite Instability Mismatch Repair Modeling Modification Mus Oncogenic Oncoproteins Organoids Pathway interactions Pattern Phenotype Population Positioning Attribute Prevalence Process Proteins Public Health Reporter Reporting Repression Research Project Grants Role Side Signal Transduction Site Small Interfering RNA System Testing Therapeutic Therapeutic Agents Tissue Microarray Tissues Transcriptional Regulation Treatment Effectiveness Tumor Suppressor Genes Tumor Tissue Woman Work Xenograft Model biobank cell type colon cancer patients colon tumorigenesis colorectal cancer treatment combinatorial demethylation epigenetic regulation epigenome gene product gene repression genome wide screen genome-wide in vivo insight intestinal epithelium knock-down men methylation pattern new therapeutic target novel overexpression patient tolerability programs promoter recruit success therapeutic target tumor tumor growth tumor initiation tumor progression tumorigenesis ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY Alterations to the normal DNA methylation patterns that regulate all chromatin-templated processes is a hallmark of cancer. Global DNA hypomethylation and local hypermethylation contribute to malignant transformation and the silencing of tumor suppressor genes (TSGs). Specific patterns of DNA hypermethylation are particularly present in a subclass of proximal colorectal cancers (CRC). These right-sided colorectal tumors often present with the CpG Island Methylator Phenotype (CIMP) in which many normally unmethylated promoter CpG islands are hypermethylated with high consistency and frequency. How these abnormal DNA methylation patterns are established and propagated remains unclear, while therapeutic agents intended to reverse DNA hypermethylation do not currently meet the needs of CRC patients. One protein with appealing attributes that may explain how DNA hypermethylation occurs in CRC is the E3 ligase and epigenetic regulator UHRF1. UHRF1 directs DNA methylation through recruitment of the maintenance DNA methyltransferase DNMT1 to newly replicated DNA. Evidence suggests UHRF1 is overexpressed and its function in DNA methylation is misappropriated in many cancers, including CRC. The objective of this proposal is to define the subclass of CRCs influenced by high UHRF1 levels and determine the mechanism through which UHRF1 contributes to CRC by altering DNA methylation levels and patterns. Aim 1 will identify the subclass of CRC most associated with high UHRF1 expression. This is critical to determining the CRC context for which inhibition of UHRF1 would have therapeutic benefit. This Aim will use primary human colon tumor tissue to segregate UHRF1-high tumors with epigenetic phenotypes. Aim 2 addresses the role of UHRF1 in colon tumor formation and maintenance. This aim will utilize an ex vivo model system of intestinal organoids derived from mouse intestinal epithelia. This system allows for precise control of the onset of an intestinal tumor phenotype to facilitate understanding of the contribution of UHRF1 to either tumor initiation or maintenance and changes in DNA methylation during this course. Finally, Aim 3 queries other gene targets identified to regulate the epigenetic-mediated silencing of TSGs. These targets were determined through a genome-wide screen and include both known epigenetic regulators and proteins previously unknown to regulate TSG silencing. As reversal of DNA hypermethylation is necessary for reactivation of TSGs, a long-term goal of this project is to gain a better understanding of the mechanisms necessary for reactivating TSGs that have been epigenetically silenced and using that information to refine CRC treatments. Thus, this proposal will address in which genetic/epigenetic subclass and at what point in tumor formation UHRF1 is important, in addition to better understanding TSG silencing through epigenetic modifications. This has high relevance to public health given the prevalence of CRC and the critical need for identifying potential therapeutic targets to reverse abnormal DNA methylation and TSG silencing in CRC.

项目概要调节所有染色质模板过程的正常 DNA 甲基化模式的改变是一个标志癌症。整体DNA低甲基化和局部高甲基化有助于恶性转化和肿瘤抑制基因（TSG）的沉默。 DNA 高甲基化的具体模式特别是存在于近端结直肠癌 (CRC) 的一个亚类中。这些右侧结直肠肿瘤经常出现具有 CpG 岛甲基化表型 (CIMP)，其中许多正常情况下未甲基化的启动子 CpG 岛高度甲基化且具有高一致性和高频率。这些异常的 DNA 甲基化模式是如何发生的其建立和传播仍不清楚，而旨在逆转 DNA 的治疗剂高甲基化目前不能满足CRC患者的需求。一种具有吸引人特性的蛋白质 E3 连接酶和表观遗传调节因子 UHRF1 可以解释 CRC 中 DNA 高甲基化的发生。超高频RF1 通过招募维持 DNA 甲基转移酶 DNMT1 来指导 DNA 甲基化复制的DNA。有证据表明 UHRF1 过度表达，其在 DNA 甲基化中的功能被滥用于许多癌症，包括结直肠癌。该提案的目标是定义以下子类： CRC 受高 UHRF1 水平影响并确定 UHRF1 促进的机制 CRC 通过改变 DNA 甲基化水平和模式。目标 1 将识别最相关的 CRC 子类具有高 UHRF1 表达。这对于确定抑制 UHRF1 的 CRC 背景至关重要有治疗作用。该目标将使用原代人结肠肿瘤组织来分离 UHRF1 高肿瘤具有表观遗传表型。目标 2 探讨 UHRF1 在结肠肿瘤形成和维持中的作用。这 Target 将利用源自小鼠肠上皮的肠类器官离体模型系统。这系统可以精确控制肠道肿瘤表型的发生，以促进对肠道肿瘤表型的理解 UHRF1 对肿瘤发生或维持的贡献以及在此期间 DNA 甲基化的变化课程。最后，目标 3 查询了其他已确定的基因靶标，以调节表观遗传介导的沉默 TSG。这些目标是通过全基因组筛选确定的，包括已知的表观遗传之前未知的调节 TSG 沉默的调节因子和蛋白质。由于 DNA 高甲基化的逆转是对于重新激活 TSG 来说是必要的，该项目的长期目标是更好地了解重新激活已在表观遗传上沉默的 TSG 并使用该信息所需的机制完善 CRC 治疗方法。因此，该提案将解决哪个遗传/表观遗传亚类以及在什么时候除了通过表观遗传学更好地了解 TSG 沉默之外，UHRF1 在肿瘤形成中也很重要修改。考虑到结直肠癌的患病率和迫切需要，这与公共卫生高度相关确定逆转 CRC 中异常 DNA 甲基化和 TSG 沉默的潜在治疗靶点。