Epigenetic regulation of cancer/germ-line antigen gene expression

描述（由申请人提供）：表观遗传变化，特别是DNA甲基化的改变，至少在两个方面有助于肿瘤的发生。首先，肿瘤中整体DNA甲基化降低，导致基因异常激活和基因组不稳定。其次，CpG岛启动子高度甲基化，导致转录沉默和肿瘤抑制基因的功能失活。除了DNA甲基化的变化外，在人类癌症中还观察到其他重要的表观遗传变化，包括组蛋白修饰模式和组蛋白修饰酶的改变。我们的长期目标是了解在人类癌症中启动和维持异常表观遗传状态的分子机制。为了实现这一目标，我们正在利用癌症/生殖系（CG）抗原基因作为模型。CG抗原是一个有趣的基因家族，其在人类癌症中的异常表达似乎是由表观遗传失调引起的。此外，CG抗原是hla限制性肿瘤抗原，可在癌症患者中引发体液和细胞介导的免疫反应；CG抗原导向疫苗目前正在进行大量的人体临床试验。因此，除了作为理解癌症表观遗传失调的模型外，CG抗原在临床上也具有相关性。我们假设CG抗原基因的表达是通过特异性DNA甲基转移酶（dnmt）和组蛋白甲基转移酶的作用进行表观遗传调控的。为了验证这一假设，我们将追求四个互补和统一的具体目标：1)确定DNMTs抑制人类癌细胞中CG抗原基因表达的机制；2)明确人癌细胞中控制CG抗原基因表达的组蛋白H3尾赖氨酸修饰；3)确定组蛋白甲基转移酶G9a和Eu-HMTasel在人癌细胞中CG抗原基因调控中的作用；4)确定NY-ESO-1表达是否与上皮性卵巢癌DNA低甲基化相关。这项研究将通过提高我们对为什么只有某些患者表达临床上重要的癌症疫苗靶点的理解来影响公共卫生。此外，该研究将为了解结果和改进卵巢癌临床疫苗试验的未来设计提供关键信息。

DESCRIPTION (provided by applicant): Epigenetic changes, particularly alterations in DNA methylation, contribute to oncogenesis in at least two respects. First, overall DNA methylation is reduced in tumors, which leads to aberrant gene activation and genomic instability. Second, CpG island promoters become hypermethylated, which leads to transcriptional silencing and the functional inactivation of tumor suppressor genes. In addition to changes in DNA methylation, other important epigenetic changes have been observed in human cancer, including alterations in histone modification patterns and histone modifying enzymes. Our long-term objective is to understand the molecular mechanisms that initiate and maintain abnormal epigenetic states in human cancer. To meet this objective, we are utilizing cancer/germ-line (CG) antigen genes as models. CG antigens are an intriguing gene family whose aberrant expression in human cancer appears to result from epigenetic deregulation. In addition, CG antigens are HLA-restricted tumor antigens that trigger humoral and cell- mediated immune responses in cancer patients; CG antigen directed vaccines are currently in numerous human clinical trials. Thus, in addition to serving as a model for understanding epigenetic deregulation in cancer, CG antigens are clinically relevant. We hypothesize that CG antigen gene expression is epigenetically regulated by the action of specific DNA methyltransferases (DNMTs) and histone methyltransferases. To test this hypothesis, we will pursue four complementary and unified specific aims: 1) Determine the mechanism by which DNMTs repress CG antigen gene expression in human cancer cells; 2) Define the histone H3 tail lysine modifications that control CG antigen gene expression in human cancer cells; 3) Ascertain the role of the histone methyltransferases G9a and Eu-HMTasel in CG antigen gene regulation in human cancer cells; and 4) Determine whether NY-ESO-1 expression is associated with DNA hypomethylation in epithelial ovarian cancer. This study will impact public health by improving our understanding of why only certain patients express clinically important cancer vaccine targets. Furthermore, this study will provide key information relevant for understanding the outcome and improving the future design of clinical vaccine trials for the treatment of ovarian cancer.