Genomic Methylation: A Mechanism to Alter Tumor Phenotype

描述（由申请人提供）：本研究申请的长期目标是研究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。基因调控区域CpG二核苷酸的胞嘧啶甲基化是基因沉默的重要表观遗传机制，而p53等关键转录因子的突变是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，使细胞转录重编程到接近正常状态，从而有效杀死肿瘤细胞或逆转恶性特性。本文提出了三个具体目标来解决这一假设，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扩展到其他人类癌症。

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.