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.

项目摘要改变调节所有染色质过程的正常DNA甲基化模式是一个标志癌症。全球DNA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高甲基化的特定模式特别是存在于近端结肠癌（CRC）的子类中。这些右侧结直肠肿瘤经常存在与CPG岛甲基表型（CIMP）一起，许多通常未甲基化的启动子CpG岛高甲基化，高稠度和频率。这些异常的DNA甲基化模式是如何的建立和繁殖的尚不清楚，而治疗剂旨在逆转DNA 高甲基化目前不满足CRC患者的需求。一种具有吸引力的蛋白质可以解释CRC中DNA高甲基化是如何发生的，是E3连接酶和表观遗传调节剂UHRF1。 UHRF1 通过募集维护DNA甲基转移酶DNMT1将DNA甲基化引导复制的DNA。有证据表明UHRF1过表达，其在DNA甲基化中的功能为在包括CRC在内的许多癌症中盗用。该提议的目的是定义 CRC受高UHRF1水平影响的CRC，并确定UHRF1促进的机制 CRC通过改变DNA甲基化水平和模式。 AIM 1将确定CRC的子类最相关的具有高UHRF1表达。这对于确定抑制UHRF1的CRC环境至关重要有治疗益处。该目标将使用原代人结肠肿瘤组织将UHRF1高肿瘤分离具有表观遗传表型。 AIM 2解决了UHRF1在结肠肿瘤形成和维持中的作用。这 AIM将利用源自小鼠肠上皮的肠道类器官的离体模型系统。这系统允许精确控制肠道肿瘤表型的发作，以促进对在此期间，UHRF1对肿瘤起始或维持以及DNA甲基化的变化课程。最后，AIM 3查询其他基因靶标，以调节表观遗传介导的沉默的沉默 TSG。这些靶标是通过全基因组筛选确定的，并包括已知的表观遗传学调节剂和蛋白质以前未知无法调节TSG沉默。由于DNA高甲基化的逆转为 TSG重新激活所必需的，该项目的长期目标是更好地了解重新激活已经表观遗传沉默的TSG所需的机制，并使用该信息完善CRC治疗。因此，该建议将解决哪种遗传/表观遗传亚类以及什么时候在肿瘤形成中，UHRF1很重要，除了更好地理解通过表观遗传学的TSG沉默修改。鉴于CRC的流行和对公共卫生的关键，这与公共卫生具有很高的相关性鉴定潜在的治疗靶标，以反向CRC中的异常DNA甲基化和TSG沉默。