The Basic and Translational Implication of SIRT1 and DNMT1 in Cancer

SIRT1 和 DNMT1 在癌症中的基本和转化意义

• 批准号: 8658413
• 负责人: EDWARD SETO
• 金额: $ 33.91万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-09 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8658413
• 关键词: Acetylation; Adult; Aging; Antineoplastic Agents; Basic Science; Biochemical Process; Biological; Biological Process; CDH1 gene; Cancer Patient; Catalytic Domain; Clinical; Clinical Trials; DNA Methylation; DNA Methyltransferase; DNA Modification Methylases; Deacetylation; Development; Diagnostic; ESR1 gene; Embryonic Development; Enzymes; Epigenetic Process; Fostering; Future; Gene Expression; Gene Silencing; Genes; Genetic Transcription; Goals; Growth; Health; Histone Deacetylase; Histone Deacetylation; Histones; Human; Hypermethylation; In Vitro; Knowledge; Laboratories; Lead; Link; Lysine; Malignant Neoplasms; Malignant neoplasm of lung; Methylation; Methyltransferase; Mus; Neoplasm Metastasis; Oncogenic; Pathogenesis; Pathology; Pathway interactions; Patients; Play; Post-Translational Protein Processing; Post-Translational Regulation; Prevention; Property; Proteins; Public Health; Role; Science; Signal Transduction; Site; System; Testing; Therapeutic; Translational Research; Treatment Efficacy; Tumor Suppressor Genes; Tumor Suppressor Proteins; Work; Xenograft Model; base; cancer diagnosis; cancer gene expression; cancer therapy; cancer type; cell transformation; clinically relevant; gene repression; human subject; improved; in vivo; inhibitor/antagonist; innovation; insight; lung xenograft; mouse model; novel; overexpression; patient oriented research; preclinical study; prognostic; promoter; research study; treatment strategy; tumor; tumor growth; tumor progression

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.

描述（由申请人提供）：DNA 甲基化和组蛋白脱乙酰化是控制基因表达的不同生化过程。 DNA 甲基化是抑制基因转录的常见表观遗传学信号，而组蛋白脱乙酰化同样会抑制转录，但既可以是表观遗传学现象，也可以是非表观遗传学现象。此应用的目的是增进对负责脱乙酰化和甲基化的两种关键酶 SIRT1 和 DNMT1 的基本了解，并将知识从 SIRT1/DNMT1 的基础研究成果转移到临床和面向患者的研究。该项目由三个高度互动且相互依赖的目标组成。目标 1 将检验 SIRT1 调节 DNMT1 的活动和功能的假设。这项工作有可能揭示 DNA 甲基化与其他表观遗传信号，特别是组蛋白脱乙酰化紧密相关。此外，这些研究可能会揭示 SIRT1 调节组蛋白脱乙酰化之外的表观遗传变化的另一种新机制。目标 2 将重点关注在 SIRT1 存在和不存在的情况下，系统分析 DNMT1 调节的癌症相关基因的甲基化状态。这一目标的结果可以使人们更好地了解关键的表观遗传调节因子如何促进癌症的发病机制和进展。目标 3 将检验 SIRT1 和 DNMT1 在已形成肺癌的生长控制中发挥作用的假设。将分析 SIRT1 和 DNMT1 抑制剂作为潜在抗癌药物的功效。最后一个目标的工作是转化性的，并且能够提出可在未来临床试验中提出的新治疗策略。尽管严格的 SIRT1 和 DNMT1 分析的共同主题在所有目标中都引起共鸣，但每个目标都提出了不同但互补的问题，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潜在的诊断以及治疗癌症的治疗方法。总之，该项目将利用基于实验室的科学、癌症患者和相关网络，通过基础和转化研究帮助推进癌症的治愈。