Genomic Methylation: A Mechanism to Alter Tumor Phenotype

基因组甲基化：改变肿瘤表型的机制

• 批准号: 7126006
• 负责人: Bernard W FUTSCHER
• 金额: $ 24.48万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7126006
• 关键词: 5 methylcytosine; DNA methylation; acetylation; amidohydrolases; breast neoplasms; chromatin; clinical research; enzyme activity; gene induction /repression; genetic promoter element; histones; neoplasm /cancer genetics; protease inhibitor; serine proteinases; tissue /cell culture; transcription factor; tumor suppressor genes

DESCRIPTION (provided by applicant): The long term objective of this research application is to examine the epigenetic mechanisms that participate in human cancer, and to determine how distinct genetic mutations cooperate and/or influence epigenetic control. Cytosine methylation of CpG dinucleotides in gene regulatory regions is an important epigenetic mechanism involved in gene silencing, whereas, mutations in critical transcription factors, such as p53, is an example of a genetic mechanism involved in silencing target genes. We provide evidence that aberrant cytosine methylation and p53 mutation can cooperate to silence genes with tumor suppressor function. We hypothesize pharmacologic strategies that target epigenetic and genetic lesions can synergize to transcriptionally reprogram cells to a near normal state that will result in efficient tumor cell kill or reversal of malignant properties. Three Specific Aims are proposed to address the hypothesis and investigate in greater detail the cooperation between genetic and epigenetic mechanisms in the control of gene expression. Studies will focus on human breast cancer; however, the general rules identified will likely extend to other human cancers. 1) Determine if p53 plays a role in the maintenance of the unmethylated state of target gene promoters. 2) Define further the mechanism by which reversal of genetic and epigenetic lesions synergize to reactivate silenced genes. 3) Identify new genes that are controlled by 5-methylcytosine in breast cancer.

描述（由申请人提供）：本研究申请的长期目标是检查参与人类癌症的表观遗传机制，并确定不同的基因突变如何合作和/或影响表观遗传控制。基因调控区中 CpG 二核苷酸的胞嘧啶甲基化是参与基因沉默的重要表观遗传机制，而关键转录因子（例如 p53）的突变是参与靶基因沉默的遗传机制的一个例子。我们提供的证据表明，异常的胞嘧啶甲基化和 p53 突变可以协同沉默具有肿瘤抑制功能的基因。我们假设针对表观遗传和遗传病变的药理学策略可以协同作用，将细胞转录重编程到接近正常的状态，从而有效杀死肿瘤细胞或逆转恶性特性。提出了三个具体目标来解决这一假设，并更详细地研究遗传和表观遗传机制在基因表达控制中的合作。研究将集中于人类乳腺癌；然而，所确定的一般规则可能会扩展到其他人类癌症。 1) 确定p53是否在维持靶基因启动子非甲基化状态中发挥作用。 2) 进一步定义逆转遗传和表观遗传损伤协同作用以重新激活沉默基因的机制。 3) 鉴定乳腺癌中受 5-甲基胞嘧啶控制的新基因。