The Basic and Translational Implication of SIRT1 and DNMT1 in Cancer

描述（由申请人提供）：DNA甲基化和组蛋白去乙酰化是控制基因表达的不同生化过程。虽然DNA甲基化是一种常见的抑制基因转录的表观遗传学信号，但组蛋白去乙酰化同样抑制转录，但可以是表观遗传学和非表观遗传学现象。本申请的目的是促进对负责去乙酰化和甲基化的两个关键酶SIRT1和DNMT1的基本了解，并将SIRT1/DNMT1的基础研究成果转移到临床和面向患者的研究中。该项目由三个高度互动和相互依存的目标组成。目的1将验证SIRT1调节DNMT1的活性和功能的假设。这项工作有可能揭示DNA甲基化与其他表观遗传信号密切相关，特别是组蛋白去乙酰化。此外，这些研究可能揭示SIRT1调节组蛋白去乙酰化以外的表观遗传变化的另一种新机制。Aim 2将侧重于在SIRT1存在和不存在的情况下，对dnmt1调控的癌症相关基因的甲基化状态进行系统分析。这一目标的结果可以更好地理解关键的表观遗传调节因子如何促进癌症的发病和进展。目的3将验证SIRT1和DNMT1在已建立的肺癌的生长控制中发挥作用的假设。分析SIRT1和DNMT1抑制剂作为潜在抗癌药物的疗效。最后一个目标的工作是转化的，并且有能力提出新的治疗策略，可以在未来的临床试验中提出。尽管严格的SIRT1和DNMT1分析的共同主题在所有目标中都有共鸣，但在每个目标中都提出了不同但互补的问题集，最终目标是彻底了解SIRT1/DNMT1的功能和临床相关性，并最终将这些知识应用于治疗癌症的潜在诊断和治疗方法。总之，该项目将通过利用实验室科学、癌症患者和相关网络，通过基础研究和转化研究，帮助推进癌症的治愈。

DESCRIPTION (provided by applicant): DNA methylation and histone deacetylation are distinct biochemical processes that control gene expression. While DNA methylation is a common epigenetics signal that inhibits gene transcription, histone deacetylation similarly represses transcription but can be both epigenetics and non-epigenetics phenomena. The objective of this application is to advance the basic understanding of two key enzymes responsible for deacetylation and methylation, SIRT1 and DNMT1, and to transfer the knowledge from basic research findings of SIRT1/DNMT1 to clinical and patient oriented research. The project consists of three highly interactive and interdependent aims. Aim 1 will test the hypothesis that SIRT1 regulates the activities and functions of DNMT1. The proposed work has potential to reveal that DNA methylation is tightly linked to other epigenetic signals, particularly histone deacetylation. Also, these studies may uncover an alternative, novel mechanism by which SIRT1 regulates epigenetic changes beyond the deacetylation of histones. Aim 2 will focus on a systematic analysis of methylation status in DNMT1-regulated cancer-related genes, in the presence and absence of SIRT1. The results from this aim can lead to a better understanding of how key epigenetic regulators contribute to the pathogenesis and progression of cancer. Aim 3 will test the hypothesis that SIRT1 and DNMT1 play a role in the growth control of established lung cancers. The efficacy of SIRT1 and DNMT1 inhibitors as potential anti- cancer drugs will be analyzed. The work in this last aim is translational and has the ability to suggest novel treatment strategies that can be proposed in future clinical trials. Although the common theme of rigorous SIRT1 and DNMT1 analysis resonates in all aims, different yet complementary sets of questions are raised in each aim with the ultimate goal of thoroughly understanding the functions and clinical relevance of SIRT1/DNMT1 and eventually applying that knowledge into potential diagnostic and therapeutic approaches for the treatment of cancer. Together, this project will help advance the cure of cancer through basic and translational research by utilizing laboratory-based science, cancer patients, and related networks.