Epigenetic regulation of cancer/germ-line antigen gene expression

表观遗传变化，特别是 DMA 甲基化的改变，至少在两个方面导致肿瘤发生 尊重。首先，肿瘤中整体 DMA 甲基化减少，这导致异常基因激活和 基因组不稳定。其次，CpG 岛启动子变得高度甲基化，从而导致转录 肿瘤抑制基因的沉默和功能失活。除了DNA的改变 甲基化，在人类癌症中观察到其他重要的表观遗传变化，包括改变 组蛋白修饰模式和组蛋白修饰酶。我们的长期目标是了解 启动和维持人类癌症异常表观遗传状态的分子机制。见面 为了实现这一目标，我们利用癌症/种系 (CG) 抗原基因作为模型。 CG抗原是 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引起的 放松管制。此外，CG抗原是HLA限制性肿瘤抗原，可触发体液和细胞- 介导癌症患者的免疫反应； CG抗原定向疫苗目前有多种 人体临床试验。因此，除了作为理解表观遗传失调的模型外， 癌症、CG抗原具有临床相关性。我们假设CG抗原基因表达是 通过特定 DNA 甲基转移酶 (DNMT) 和组蛋白的作用进行表观遗传调控 甲基转移酶。为了检验这一假设，我们将追求四个互补且统一的具体目标：1） 确定 DNMT 抑制人类癌细胞中 CG 抗原基因表达的机制； 2） 定义控制人类癌症中 CG 抗原基因表达的组蛋白 H3 尾部赖氨酸修饰 细胞； 3) 确定组蛋白甲基转移酶G9a和Eu-HMTasel在CG抗原基因中的作用 对人类癌细胞的调节； 4) 确定 NY-ESO-1 表达是否与 DNA 相关 上皮性卵巢癌中的低甲基化。这项研究将通过改善我们的健康状况来影响公众健康 了解为什么只有某些患者表达临床上重要的癌症疫苗靶标。此外， 这项研究将提供与了解结果和改善未来相关的关键信息 治疗卵巢癌的临床疫苗试验的设计。

Epigenetic changes, particularly alterations in DMAmethylation, contribute to oncogenesis in at least two respects. First, overall DMA 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.