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。虽然DNA甲基化是抑制基因转录的常见表观遗传学信号，但组蛋白脱乙酰化类似地抑制转录，但既可以表观遗传学，又可以是非基因遗传学现象。该应用的目的是将两种负责脱乙酰化和甲基化的关键酶（SIRT1和DNMT1）提高基本理解，并将知识从SIRT1/DNMT1的基础研究发现转移到面向临床和患者的研究。该项目由三个高度互动和相互依存的目标组成。 AIM 1将检验SIRT1调节DNMT1活动和功能的假设。提出的工作有可能揭示DNA甲基化与其他表观遗传信号，尤其是组蛋白脱乙酰化紧密相关。同样，这些研究可能会发现一种替代的新型机制，通过该机制，SIRT1通过该机制调节超出组蛋白脱乙酰化的表观遗传变化。 AIM 2将集中于在存在和不存在SIRT1的情况下DNMT1调节的癌症相关基因中甲基化状态的系统分析。该目标的结果可以更好地了解关键表观遗传调节剂如何促进癌症的发病机理和进展。 AIM 3将检验以下假设：SIRT1和DNMT1在已建立的肺癌的生长控制中起作用。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翻译，并且能够提出可以在以后的临床试验中提出的新型治疗策略。尽管严格的SIRT1和DNMT1分析的共同主题在所有目标中都引起了共鸣，但在每个目标中都提出了不同但互补的问题集，其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和治疗方法中，以治疗癌症。通过利用基于实验室的科学，癌症患者和相关网络，该项目将通过基础和转化研究来帮助通过基础和转化研究来促进癌症的治疗。