Genomic Methylation: A Mechanism to Alter Tumor Phenotype

描述(申请人提供)：这项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。CpG二核苷酸在基因调控区的胞嘧啶甲基化是基因沉默的重要表观遗传学机制，而关键转录因子的突变，如P53，是涉及沉默靶基因的遗传机制的一个例子。我们提供的证据表明，胞嘧啶甲基化异常和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损伤的药物策略可以协同作用，在转录上将细胞重新编程到接近正常的状态，从而导致有效的肿瘤细胞杀伤或逆转恶性特性。提出了三个具体的目标来解决这一假说，并更详细地研究基因表达控制中遗传和表观遗传机制之间的合作。研究将集中在人类乳腺癌上；然而，确定的一般规则可能会延伸到其他人类癌症。 1)确定P53是否在维持靶基因启动子的非甲基化状态中起作用。 2)进一步确定逆转遗传和表观遗传损伤以重新激活沉默基因的机制。 3)发现乳腺癌中受5-甲基胞嘧啶控制的新基因。

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.