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甲基化的变化，至少在两个方面有助于肿瘤发生。首先，肿瘤整体DNA甲基化减少，导致基因异常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甲基化的变化外，在人类癌症中还观察到了其他重要的表观遗传学变化，包括组蛋白修饰模式和组蛋白修饰酶的变化。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。为了达到这一目标，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去调控的结果。此外，CG抗原是人类白细胞抗原限制性的肿瘤抗原，可在癌症患者中触发体液和细胞免疫反应；CG抗原导向的疫苗目前正在进行大量的人类临床试验。因此，除了作为理解癌症表观遗传去调控的模型外，CG抗原在临床上也是相关的。我们假设CG抗原基因的表达受特定DNA甲基转移酶(DNMT)和组蛋白甲基转移酶作用的表观遗传调控。为了验证这一假说，我们将追求四个互补和统一的特定目标：1)确定DNMT抑制人癌细胞CG抗原基因表达的机制；2)确定控制人癌细胞CG抗原基因表达的组蛋白H3尾部赖氨酸修饰；3)确认组蛋白甲基转移酶G9a和EU-HMTasel在人癌细胞CG抗原基因调控中的作用；以及4)确定NY-ESO-1的表达是否与上皮性卵巢癌中DNA低甲基化有关。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众健康。此外，这项研究将为了解结果和改进未来卵巢癌临床疫苗试验的设计提供相关的关键信息。

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.