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Bmi-1 and Skin Cancer Prevention

Bmi-1 和皮肤癌预防

基本信息

批准号：
8284462
负责人：
Richard L. Eckert
金额：
$ 41.62万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8284462
关键词：
Address Apoptosis Area B-Lymphocytes Binding Binding Sites Biological Models CDKN2A gene Cell Cycle Progression Cell Death Cell Differentiation process Cell Line Cell Nucleus Cell Proliferation Cell Survival Cell division Cells Chemoprevention Chemopreventive Agent Chromatin Complex Cyclin-Dependent Kinases Cyclins Deacetylation Development Diet Drosophila genus Epidermis Epigallocatechin Gallate Epigenetic Process Epithelial Event Family Gene Expression Gene Expression Regulation Gene Proteins Gene Silencing Gene Targeting Genes Goals Green tea Hematopoietic Histone Deacetylase Histone H3 Histones Homologous Gene Human In Vitro Incidence Lymphomagenesis Lysine Malignant Neoplasms Measures Mediating Mediator of activation protein Messenger RNA Methylation Modeling Moloney Leukemia Virus Monitor Multiprotein Complexes Mus Neurons PRC1 Protein Phosphorylation Polycomb Predisposition Preventive Property Proteins RNA chemical synthesis Recruitment Activity Regulation Response Elements Role Site Skin Skin Cancer Skin Carcinogenesis Skin Neoplasms Stem cells System Testing Tumor Tissue Ultraviolet B Radiation Ultraviolet Rays Virus Integration abstracting anti-cancer therapeutic base cancer cell cancer chemoprevention cancer stem cell cancer therapy carcinogenesis chromatin modification design functional status gallocatechol genetic regulatory protein in vivo in vivo Model innovation interest keratinocyte neoplastic cell novel overexpression p19ARF polyphenol prevent protein complex protein expression research study skin cancer prevention therapeutic target tumor vector

项目摘要

Abstract From the perspective of cancer chemoprevention, an important strategy is to inhibit cell division and/or reduce the survival of cancer cells or to make the cells more sensitive to co-therapy. This goal can be achieved by reducing the level or activity of cell survival proteins. The polycomb group (PcG) genes encode an important group of cell survival proteins, which were originally discovered to enhance stem cell survival. These proteins act, via global epigenetic (chromatin modification) mechanisms, to suppress gene expression and enhance cell survival. They are key epigenetic controllers. Because they promote cell proliferation and survival and operate via an epigenetic mechanism, PcG proteins are regarded as having great potential as anti-cancer therapeutic targets. In spite of the potential importance of the PcG genes in enhancing cancer cell survival, the role of diet-derived chemopreventive agents in modulating their function has not been addressed. Bmi-1 is a polycomb protein that is expressed at high levels in some tumor types. Our preliminary studies show that Bmi-1 is markedly overexpressed in skin cancer cells and tumors, and that targeted overexpression of Bmi-1 enhances skin cancer cell survival. In addition, our studies show that the bioactive polyphenol present in green tea, (-)-epigallocatechin-3-gallate (EGCG), reduces Bmi-1 level and that this reduction is associated with reduced skin cancer cell proliferation and survival. These findings suggest that chemopreventive agents may act to reduce skin cancer by reducing Bmi-1 level and activity. The idea that chemopreventive agents may act by interfering with PcG gene- dependent epigenetic regulatory mechanisms has not been widely considered or studied. The major goal of this proposal is to understand how EGCG acts to regulate Bmi-1 level and activity in skin cancer. The studies outlined in Specific Aim 1 are designed to determine the mechanism(s) whereby EGCG reduces Bmi-1 level and activity. The experiments outlined in Specific Aim 2 are designed to understanding how the EGCG-dependent reduction in Bmi-1 level results in reduced skin cancer cell survival. Specific Aim 3 focuses on the contribution of other PcG gene products that are part of the Bmi-1 multiprotein complex, and Specific Aim 4 examines the in vivo role of Bmi-1 using an epidermis-targeted Bmi-1 overexpression model to study UVB-dependent skin carcinogenesis. Narrative The polycomb (PcG) proteins act via epigenetic (chromatin modification) mechanisms to enhance cancer cell survival. Because of this property, PcG proteins are regarded as having great potential as anti-cancer therapy targets. Green tea polyphenols are important diet-derived cancer preventive agents that prevent UV light-dependent skin cancer. Our studies show that an active agent in green tea reduces polycomb gene expression in skin cancer cells making them more susceptible to cell death. Our goal is to determine whether suppression of the level and function of the Bmi-1 PcG protein is a mechanism whereby green tea polyphenols inhibit the development of ultraviolet light-dependent skin cancer. These studies are regarded as innovative because the impact of chemopreventive agents on this important type of epigenetic regulation has not been previously considered for study.

抽象的从癌症化学预防的角度来看，一个重要的策略是抑制细胞分裂和/或降低癌细胞的存活率或使细胞对联合治疗更加敏感。这个目标可以是通过降低细胞存活蛋白的水平或活性来实现。多梳族 (PcG) 基因编码一组重要的细胞存活蛋白，最初发现这些蛋白可以增强干细胞生存。这些蛋白质通过全局表观遗传（染色质修饰）机制发挥作用，抑制基因表达并增强细胞存活。它们是关键的表观遗传控制器。因为它们促进细胞 PcG 蛋白被认为具有增殖和存活并通过表观遗传机制发挥作用作为抗癌治疗靶点的巨大潜力。尽管 PcG 基因在增强癌细胞存活率，饮食来源的化学预防剂在调节其功能中的作用尚未得到解决。 Bmi-1是一种多梳蛋白，在某些肿瘤中高水平表达类型。我们的初步研究表明，Bmi-1 在皮肤癌细胞中显着过度表达，并且肿瘤，并且 Bmi-1 的靶向过度表达可增强皮肤癌细胞的存活率。此外，我们的研究表明，绿茶中存在的生物活性多酚，(-)-表没食子儿茶素-3-没食子酸酯 (EGCG)，降低 Bmi-1 水平，这种降低与皮肤癌细胞增殖减少有关生存。这些发现表明，化学预防剂可能通过减少皮肤癌的发生来起到减少皮肤癌的作用。 Bmi-1 水平和活动。化学预防剂可能通过干扰 PcG 基因发挥作用的想法依赖的表观遗传调控机制尚未得到广泛考虑或研究。主要目标该提案的目的是了解 EGCG 如何发挥作用来调节皮肤癌中的 Bmi-1 水平和活性。这具体目标 1 中概述的研究旨在确定 EGCG 减少的机制 Bmi-1 水平和活动。具体目标 2 中概述的实验旨在了解如何 EGCG 依赖性 Bmi-1 水平降低会导致皮肤癌细胞存活率降低。具体目标 3 重点关注属于 Bmi-1 多蛋白复合物一部分的其他 PcG 基因产物的贡献，具体目标 4 使用表皮靶向的 Bmi-1 过表达来检查 Bmi-1 的体内作用研究 UVB 依赖性皮肤癌发生的模型。叙述多梳 (PcG) 蛋白通过表观遗传（染色质修饰）机制发挥作用，增强癌症的发生细胞存活。由于这种特性，PcG 蛋白被认为具有巨大的抗癌潜力治疗目标。绿茶多酚是重要的饮食来源的癌症预防剂，可预防紫外线依赖性皮肤癌。我们的研究表明绿茶中的活性剂可减少多梳皮肤癌细胞中的基因表达使它们更容易细胞死亡。我们的目标是确定抑制 Bmi-1 PcG 蛋白的水平和功能是否是绿茶的一种机制多酚可抑制紫外线依赖性皮肤癌的发展。这些研究被视为之所以具有创新性，是因为化学预防剂对这种重要类型的表观遗传的影响此前并未考虑进行研究。