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: 8345095
• 负责人: EDWARD SETO
• 金额: $ 34.96万
• 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/8345095
• 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. PUBLIC HEALTH RELEVANCE: The proposed project has potential to improve public health in several ways. First, the proposed work to study SIRT1 and DNMT1 has the potential to reveal novel etiological and pathogenesis pathways for some cancers. SIRT1 has oncogenic properties but, paradoxically, can act as a tumor suppressor. Inactivation of DNMT1 during embryogenesis causes tumors in adult mice, and overexpression of DNMT1 transforms cells. Second, the proposed studies potentially can lead to better prevention and diagnosis of cancer. SIRT1 may act as a potent regulator of aging-associated pathologies, including several types of cancer. Studies in this application may lead to prognostic and predictive information for cancer and help develop therapeutics that will extend aging and reduce malignancy. Finally, the proposed work may contribute to better treatments and cure of cancer. Histone deacetylases and DNA methyltransferases are potentially good targets for anti-cancer therapy. Our work to elucidate the efficacy of SIRT1 and DNMT1 inhibitors as potential anti-cancer drugs fits well with the ultimate goal to help alleviate human suffering from cancer.

描述(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，但组蛋白去乙酰化类似地抑制转录，但可以是表观遗传学和非表观遗传学现象。这项应用的目的是促进对负责脱乙酰基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以患者为中心的研究中。该项目由三个高度互动和相互依存的目标组成。目的1验证SIRT1调控DNMT1活性和功能的假说。这项拟议的工作有可能揭示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，这些研究可能会揭示SIRT1调节组蛋白脱乙酰化以外的表观遗传学变化的另一种新机制。目的2将集中于在存在和不存在SIRT1的情况下，对DNMT1调节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导致更好地理解关键的表观遗传调节因子如何在癌症的发病和进展中发挥作用。目的3将验证SIRT1和DNMT1在已建立的肺癌生长控制中发挥作用的假设。SIRT1和DNMT1抑制剂作为潜在的抗癌药物的有效性将被分析。这最后一个目标的工作是翻译的，并有能力提出新的治疗策略，可以在未来的临床试验中提出。虽然严格的SIRT1和DNMT1分析的共同主题在所有目标中都有共鸣，但每个目标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潜在的癌症诊断和治疗方法。总而言之，该项目将利用以实验室为基础的科学、癌症患者和相关网络，通过基础和转化性研究，帮助推进癌症的治疗。 公共卫生相关性：拟议的项目有可能在几个方面改善公共卫生。首先，拟议的研究SIRT1和DNMT1的工作有可能揭示一些癌症的新病因和发病机制。SIRT1具有致癌特性，但矛盾的是，它可以作为一种肿瘤抑制因子。DNMT1在胚胎发育过程中失活会导致成年小鼠肿瘤，DNMT1的过表达会转化细胞。其次，拟议的研究可能会导致更好的癌症预防和诊断。SIRT1可能对衰老相关的病理起到强有力的调节作用，包括几种癌症。对这一应用的研究可能导致癌症的预后和预测信息，并有助于开发延长衰老和减少恶性肿瘤的治疗方法。最后，拟议的工作可能有助于更好地治疗和治愈癌症。组蛋白脱乙酰酶和DNA甲基转移酶是潜在的抗癌治疗的良好靶点。我们的工作是阐明SIRT1和DNMT1抑制剂作为潜在抗癌药物的有效性，这与帮助减轻人类癌症痛苦的最终目标非常吻合。