Epigenetic regulation of cancer/germ-line antigen gene expression

表观遗传变化，特别是DNA甲基化的变化，在至少两个 敬重。首先，在肿瘤中，总的DMA甲基化减少，这导致异常的基因激活和 基因组不稳定。第二，CpG岛启动子高甲基化，导致转录 沉默和肿瘤抑制基因的功能失活。除了DNA的变化 甲基化，在人类癌症中观察到了其他重要的表观遗传学变化，包括变化 在组蛋白修饰模式和组蛋白修饰酶中。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。相遇 本研究的目的是利用肿瘤/生殖细胞(CG)抗原基因作为模型。CG抗原是一种 耐人寻味的基因家族，其在人类癌症中的异常表达似乎是表观遗传的结果 放松管制。此外，CG抗原是一种人类白细胞抗原限制性肿瘤抗原，可触发体液和细胞免疫。 癌症患者的介导性免疫反应；CG抗原导向的疫苗目前有许多 人体临床试验。因此，除了作为理解表观遗传去监管化的模型之外， 癌症、CG抗原在临床上具有相关性。我们假设CG抗原基因的表达是 受特定DNA甲基转移酶(DNMT)和组蛋白作用的表观遗传调控 甲基转移酶。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DNMT抑制人癌细胞CG抗原基因表达的机制；2) 确定在人类癌症中控制CG抗原基因表达的组蛋白H3尾部赖氨酸修饰 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 4)确定NY-ESO-1的表达是否与DNA有关 上皮性卵巢癌中的低甲基化。这项研究将通过改善我们的 理解为什么只有某些患者表达临床上重要的癌症疫苗靶点。此外， 这项研究将提供与理解结果和改善未来相关的关键信息 卵巢癌临床疫苗试验设计。

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.