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Epigenetic regulation of cancer/germ-line antigen gene expression

癌症/种系抗原基因表达的表观遗传调控

基本信息

批准号：
8398356
负责人：
ADAM R. KARPF
金额：
$ 3.39万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-08 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8398356
关键词：
Epigenetic regulation cancer germ line

项目摘要

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.

表观遗传学变化，特别是DMA甲基化的改变，有助于至少两种肿瘤的发生。个方面首先，肿瘤中的总体DMA甲基化降低，这导致异常基因激活，基因组不稳定性第二，CpG岛启动子变得高甲基化，这导致转录抑制。沉默和肿瘤抑制基因的功能失活。除了DNA的变化之外除了甲基化之外，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。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。满足为此，我们利用癌/生殖系（CG）抗原基因作为模型。CG抗原是一种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引起的放松管制。此外，CG抗原是HLA限制性肿瘤抗原，其触发体液和细胞免疫。介导的免疫应答; CG抗原导向的疫苗目前在许多人体临床试验因此，除了作为一个模型来理解表观遗传失调，在癌症中，CG抗原是临床相关的。我们假设CG抗原基因表达是表观遗传学上受特异性DNA甲基转移酶（DNMT）和组蛋白的作用调节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抑制人癌细胞中CG抗原基因表达的机制; 2）确定控制人类癌症中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G9 a和Eu-HMTasel在CG抗原基因中的作用 4）确定NY-ESO-1表达是否与人癌细胞中的DNA表达相关。卵巢上皮癌中的低甲基化。这项研究将通过改善我们的健康状况来影响公众健康。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，委员会认为，这项研究将为了解结果和改善未来提供关键信息设计用于治疗卵巢癌的临床疫苗试验。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

BORIS/CTCFL mRNA isoform expression and epigenetic regulation in epithelial ovarian cancer.

DOI：
发表时间：
2013
期刊：
Cancer immunity
影响因子：
0
作者：
Petra A. Link;Wa Zhang;K. Odunsi;A. Karpf
通讯作者：
Petra A. Link;Wa Zhang;K. Odunsi;A. Karpf

Immunomodulatory action of SGI-110, a hypomethylating agent, in acute myeloid leukemia cells and xenografts.

SGI-110（一种低甲基化剂）在急性髓系白血病细胞和异种移植物中的免疫调节作用。

DOI：
10.1016/j.leukres.2014.09.001
发表时间：
2014
期刊：
Leukemia research
影响因子：
2.7
作者：
Srivastava,Pragya;Paluch,BenjaminE;Matsuzaki,Junko;James,SmithaR;Collamat-Lai,Golda;Karbach,Julia;Nemeth,MichaelJ;Taverna,Pietro;Karpf,AdamR;Griffiths,ElizabethA
通讯作者：
Griffiths,ElizabethA

BORIS/CTCFL expression is insufficient for cancer-germline antigen gene expression and DNA hypomethylation in ovarian cell lines.

BORIS/CTCFL 表达不足以表达卵巢细胞系中的癌症种系抗原基因表达和 DNA 低甲基化。