Role of SIRT1 in melanocyte biology and melanocyte transformation

SIRT1 在黑素细胞生物学和黑素细胞转化中的作用

基本信息

批准号：
9257364
负责人：
Nihal Ahmad
金额：
$ 31.23万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
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 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9257364
关键词：
Advocate American Joint Committee on Cancer Apoptosis Apoptotic Attention Biological Process Biology Cell Aging Cell Cycle Progression Cell Proliferation Cell Survival Cells Clinical Complex Cutaneous Melanoma DNA Damage DNA Repair Data Development Disease Progression Dissection Dysplastic Nevus E2F1 gene Ensure Epigenetic Process Event FOXO1A gene Family Gene Expression Profile Genetic Goals Histone Deacetylase Human Imaging technology Implant Knowledge Literature Malignant Neoplasms Mediating Melanoma Cell Molecular Molecular Profiling Mutation Neoplastic Cell Transformation Nevi and Melanomas Nude Mice Organism Outcome Outcome Study Phenotype Physiological Play Prevention Process Proteins Protocols documentation Regional Lymph Node Involvement Regulation Research Role Route SIRT1 gene Sirtuins Skin Specimen System TP53 gene Testing Tetracyclines Therapeutic Tissue Microarray Tissues Transcriptional Activation Tumor Promoters Tumor Suppressor Proteins base cell growth cellular longevity in vitro Model in vivo inhibitor/antagonist interest knock-down liquid crystal polymer melanocyte melanoma member neoplastic overexpression prevent programs public health relevance response small molecule transcription factor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The genetic dissection of a complex process such as melanocytic transformation is a daunting task. Indeed, different stages of differentiation of human melanocytic cells, such as normal melanocytes, nevi and melanomas representing different stages of disease progression, reflect distinct gene expression patterns. An in-depth knowledge of the genetic and epigenetic controls of cellular proliferation and cell cycle progression may provide critical information regarding the conversion of a normal melanocyte to its neoplastic phenotype. Over the past decade, SIRT1, a member of SIR2 family of sirtuin class III histone deacetylases, has garnered tremendous attention in neoplastic transformation and progression. A number of critical proteins, including p53 and FoxO transcription factors, have been identified as SIRT1 substrates. The roles and functions of SIRT1 in cancer have become extremely complex and are not well understood. Whereas a plethora of studies have shown a tumor promoter function of SIRT1, a number of studies have advocated its tumor suppressor role. It appears that SIRT1 plays dual functions in different tissue contexts depending on the spatial and temporal distribution and abundance of different SIRT1 downstream targets and factors that regulate SIRT1. The role and functional significance of SIRT1 in melanocyte biology, melanocytic transformation and progression is not clear. In our preliminary data, we have found that i) SIRT1 is expressed at much higher levels in melanoma cells and tissues, and ii) inhibition of SIRT1 results in a significant anti-proliferative response in melanoma cells. Further, the observed effects of SIRT1 inhibition were accompanied with transcriptional activation of p53. This is of particular interest because melanoma is one of the few cancers which rarely possess p53 mutations and this may provide an alternative route for altered p53 regulation without actual mutations. Thus, based on available literature and our exciting preliminary data, in this study we propose to test the hypothesis that SIRT1 plays a critical role in melanocytic transformation and melanoma survival via modulating its downstream regulation of p53, FoxO, and E2F1 transcription factors. The following aims are proposed: 1) to evaluate the expression profile of SIRT1 and its specific correlations with downstream regulators (viz. p53, FoxOs and E2F1 during melanomagenesis), and to determine if SIRT1 is involved in melanocytic transformation in an in vitro model; 2) to define the involvement of p53, FoxO and E2F1 transcription factors as downstream determinants of SIRT1 in melanocytic cells; and 3) to determine the therapeutic significance of SIRT1 inhibition in vivo in athymic nude mice implanted with melanoma cells. We expect that the outcome of studies proposed in this application may define the role and mechanism of SIRT1 in melanocyte biology, melanocytic transformation and melanoma progression. This may ultimately have therapeutic implications.

描述（由申请人提供）：黑素细胞转化等复杂过程的基因解剖是一项艰巨的任务。事实上，人类黑素细胞的不同分化阶段，例如代表疾病进展不同阶段的正常黑素细胞、痣和黑素瘤，反映了不同的基因表达模式。对细胞增殖和细胞周期进程的遗传和表观遗传控制的深入了解可以提供有关正常黑素细胞向其肿瘤表型转化的关键信息。在过去的十年中，SIRT1（sirtuin III 类组蛋白脱乙酰酶 SIR2 家族的成员）在肿瘤转化和进展中引起了极大的关注。许多关键蛋白质，包括 p53 和 FoxO 转录因子，已被确定为 SIRT1 底物。 SIRT1 在癌症中的作用和功能已变得极其复杂且尚不清楚。虽然大量研究表明 SIRT1 具有肿瘤促进作用，但许多研究主张其肿瘤抑制作用。 SIRT1 似乎在不同的组织环境中发挥双重功能，具体取决于不同 SIRT1 下游靶标和调节 SIRT1 的因素的空间和时间分布以及丰度。 SIRT1 在黑素细胞生物学、黑素细胞转化和进展中的作用和功能意义尚不清楚。在我们的初步数据中，我们发现 i) SIRT1 在黑色素瘤细胞和组织中的表达水平要高得多，ii) 抑制 SIRT1 会导致黑色素瘤细胞产生显着的抗增殖反应。此外，观察到的 SIRT1 抑制作用伴随着 p53 的转录激活。这是特别令人感兴趣的，因为黑色素瘤是少数很少具有 p53 突变的癌症之一，这可能为改变 p53 调节而无需实际突变提供替代途径。因此，基于现有文献和我们令人兴奋的初步数据，在本研究中，我们建议检验 SIRT1 通过调节 p53、FoxO 和 E2F1 转录因子的下游调节在黑素细胞转化和黑色素瘤存活中发挥关键作用的假设。提出以下目标：1）评估SIRT1的表达谱及其与下游调节因子（即黑色素瘤发生过程中的p53、FoxOs和E2F1）的特定相关性，并确定体外模型中SIRT1是否参与黑素细胞转化； 2) 定义 p53、FoxO 和 E2F1 转录因子作为黑素细胞中 SIRT1 下游决定因素的参与； 3）确定SIRT1抑制在植入黑色素瘤细胞的无胸腺裸鼠体内的治疗意义。我们期望本申请中提出的研究结果可以定义 SIRT1 在黑色素细胞生物学、黑色素细胞转化和黑色素瘤进展中的作用和机制。这最终可能具有治疗意义。