Mechanisms of tumor suppression by the chromatin deacetylase SIRT6

染色质脱乙酰酶 SIRT6 抑制肿瘤的机制

基本信息

批准号：
8689985
负责人：
David Benner Lombard
金额：
$ 16.17万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8689985
关键词：
Aneuploidy Animal Model Attenuated Cancer Etiology Carcinoma Cell Line Cells Chromatin Chromosomal Instability Chromosomal Stability Chromosomes Collaborations DNA DNA Repair Data Deacetylase Defect Disease Dissection Elements Epigenetic Process Epithelial Cells Epitopes Fibroblasts Gene Activation Gene Deletion Genome Genome Stability Goals Growth Heterochromatin Homeostasis Human Immunoprecipitation Intestinal Neoplasms Intestines Laboratories Large Intestine Carcinoma Life Link Maintenance Malignant - descriptor Malignant Neoplasms Mammals Metabolic Metastatic to Mission Mitotic Modeling Mus Oncogenes Output Pathway interactions Play Ploidies Process Property Protein Family Proteins Public Health Publishing Research Role Signal Transduction Sirtuins System Testing Tumor Burden Tumor Suppression Tumor Suppressor Genes Tumor Suppressor Proteins Work adenoma attenuation carcinogenesis cellular imaging hypoxia inducible factor 1 immortalized cell in vivo innovation insight lymph nodes molecular marker novel overexpression protein complex public health relevance research study tumor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Loss of chromosomal stability is a common feature of human carcinomas. How cells maintain chromosomal integrity is incompletely understood; however it is clear that many pathways and protein complexes are involved. Maintenance of the correct chromosomal content (euploidy) is an important contributor to overall chromosomal stability. Emerging data indicate that epigenetic silencing of pericentromeric repetitive DNA elements plays a key role in maintenance of euploidy. Defective pericentromeric silencing is sufficient to induce chromosomal instability and, in animal models, malignancy. This application focuses on novel functions for the sirtuin SIRT6 in tumor suppression, pericentromeric silencing, and ploidy maintenance. The sirtuins are a family of protein deacetylases that promote many aspects of healthspan in mammals, among them tumor suppression. The long- term goal of the laboratory is to elucidate mechanisms by which sirtuins, in particular SIRT6, promote healthspan. Recently published work by the applicant's laboratory has shown that SIRT6 functions as an intestinal tumor suppressor in humans and mice, at least in part via attenuation of MYC and HIF1 signaling. The objective of this application is to elucidate a third role of SIRT6 in tumor suppression, specifically in pericentromeric silencing and chromosomal stability. The central hypothesis of this application is that SIRT6 promotes epigenetic silencing of pericentromeric DNA to promote euploidy maintenance, a function that contributes to its tumor suppressor function. The rationale for these studies is that a mechanistic dissection of the relationships between SIRT6, pericentromeric silencing, and euploidy will contribute to an enhanced understanding of chromosomal stability overall. This work will be carried out in three Specific Aims. First, the significance of SIRT6's interactions with known chromatin silencing factors will be elucidated. Potential mitotic defects in SIRT6-deficient cells will be identified b live-cell imaging. Second, the impact of loss of SIRT6 function will be assessed in intestinal epithelial cells and adenomas with respect to malignant properties and induction of aneuploidy. Third, the ability of SIRT6 overexpression to suppress adenomatosis will be tested in vivo. The approach is innovative, in that the contribution of pericentromeric silencing to ploidy maintenance is still incompletely understood, and SIRT6 has not previously been linked to this process. The work is significant, in that it is likely to provide new insights into mechanisms of ploidy maintenance, which in turn is a major factor in overall genomic stability and tumor suppression.

描述（由申请人提供）：染色体稳定性的丧失是人类癌的常见特征。细胞如何保持染色体完整性是不完全理解的。但是，很明显，许多途径和蛋白质复合物涉及。维持正确的染色体含量（Euploidy）是总体染色体稳定性的重要原因。新兴数据表明，周围质粒重复的DNA元素的表观遗传沉默在维持平倍型中起关键作用。有缺陷的周围质粒沉默足以诱导染色体不稳定性，并且在动物模型中，恶性肿瘤。该应用集中在Sirtuin SIRT6肿瘤抑制，围层沉默和倍增性维持中的新功能上。 Sirtuins是蛋白质脱乙酰基酶的家族，可促进哺乳动物中的健康状态的许多方面，其中包括肿瘤抑制。该实验室的长期目标是阐明Sirtuins（特别是SIRT6）促进HealthSpan的机制。申请人实验室最近发表的工作表明，SIRT6在人类和小鼠中起着肠道肿瘤的抑制作用，至少部分是通过MYC和HIF1信号传导的部分作用。该应用的目的是阐明SIRT6在肿瘤抑制中的第三个作用，特别是在周围质粒沉默和染色体稳定性中。该应用的中心假设是SIRT6促进了周围质粒DNA的表观遗传沉默，以促进Euploidy维持，这一功能有助于其肿瘤抑制器功能。这些研究的基本原理是，对SIRT6，周围质粒沉默和多倍体之间关系的机理解剖将有助于加强对染色体稳定性的理解。这项工作将以三个特定的目的进行。首先，将阐明SIRT6与已知染色质沉默因子的相互作用的重要性。 SIRT6缺陷细胞中的潜在有丝分裂缺陷将被鉴定出B活细胞成像。其次，SIRT6功能丧失的影响将在肠上皮细胞和腺瘤中评估有关恶性特性和诱导非整倍性的影响。第三，将在体内测试SIRT6过表达抑制腺瘤病的能力。这种方法是创新的，因为围质粒粒沉默对倍增性维持的贡献仍然尚不完全了解，而SIRT6以前尚未与此过程有关。这项工作很重要，因为它很可能会提供对倍性维持机制的新见解，这反过来又是总体基因组稳定性和肿瘤抑制的主要因素。