Investigation of the role of the histone modifying enzyme peptidyl arginine deiminase 4 (PAD4) in breast cancer progression

组蛋白修饰酶肽基精氨酸脱亚胺酶 4 (PAD4) 在乳腺癌进展中的作用研究

• 批准号: 169659824
• 负责人: Dr. Sonja Christa Stadler
• 金额: --
• 依托单位: Institut für Laboratoriumsmedizin, Klinische Chemie und Molekulare Diagnostik
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/169659824?language=en
• 关键词: Investigation; role; histone; modifying; enzyme

Breast cancer is the most common tumor in women worldwide and disease progression still remains poorly understood. Recent studies have shown that in addition to genetic mutations, epigenetic alterations also contribute to tumorigenesis, not only at the levels of DNA methylation but also at the level of histone marks and histone modifying enzymes. The aim of this research proposal is to elucidate the role of epigenetic alteration in breast cancer, in particular the role of PAD4, an enzyme that converts histone arginine and methylarginine residues to citrulline. My preliminary data strongly suggest that PAD4 inhibits epithelial-to-mesenchymal-transition in breast cancer cells, a transition event that gives rise to invasive, tumorigenic cancer cells. My proposed studies seek to determine downstream gene targets and underlying pathways of PAD4 by performing microarray and ChIP-sequencing analyses to elucidate how this enzyme is involved preserving an epithelial cell phenotype. Moreover, I will test the hypothesis that downregulation of PAD4 and the resulting reduction of histone citrullination is part of an epithelial-tomesenchymal- transition program in invasive breast cancer cells and can be reversed by the overexpression of PAD4. The expected results of the proposed project will give rise to a better understanding of the role of histone modifications mediated by enzyme PAD4 in breast cancer and will likely be helpful for the development of novel diagnostic and therapeutic strategies in the prevention of breast cancer progression.

乳腺癌是世界范围内女性最常见的肿瘤，对疾病进展仍然知之甚少。最近的研究表明，除了基因突变外，表观遗传学改变也有助于肿瘤的发生，不仅在DNA甲基化水平上，而且在组蛋白标记和组蛋白修饰酶水平上。这项研究提案的目的是阐明表观遗传改变在乳腺癌中的作用，特别是PAD 4的作用，PAD 4是一种将组蛋白精氨酸和甲基精氨酸残基转化为瓜氨酸的酶。我的初步数据强烈表明，PAD 4抑制乳腺癌细胞中的上皮细胞向间充质细胞的转变，这是一种引起侵袭性、致瘤性癌细胞的转变事件。我提出的研究旨在通过进行微阵列和ChIP测序分析来确定PAD 4的下游基因靶点和潜在途径，以阐明这种酶如何参与保护上皮细胞表型。此外，我将检验以下假设：PAD 4的下调和由此导致的组蛋白瓜氨酸的减少是浸润性乳腺癌细胞中上皮-间充质转化程序的一部分，并且可以通过PAD 4的过表达逆转。拟议项目的预期结果将使人们更好地了解酶PAD 4介导的组蛋白修饰在乳腺癌中的作用，并可能有助于开发预防乳腺癌进展的新诊断和治疗策略。