Bmi-1 and Skin Cancer Prevention

描述(由申请人提供)： 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/或减少癌细胞的存活，或者使细胞对联合治疗更敏感。这一目标可以通过降低细胞存活蛋白的水平或活性来实现。多梳组(PcG)基因编码一组重要的细胞生存蛋白，最初被发现可提高干细胞的存活。这些蛋白质通过全球表观遗传(染色质修饰)机制抑制基因表达，提高细胞存活率。它们是关键的表观遗传控制者。由于PcG蛋白促进细胞增殖和存活，并通过表观遗传机制发挥作用，因此被认为具有巨大的抗癌治疗靶点潜力。尽管PcG基因在提高癌细胞存活方面具有潜在的重要性，但饮食衍生的化学预防药物在调节其功能方面的作用尚未得到解决。BMI-1是一种多梳蛋白，在某些肿瘤类型中高水平表达。我们的初步研究表明，BMI-1在皮肤癌细胞和肿瘤中显著过表达，靶向过表达BMI-1可以提高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，(-)-表没食子儿茶素没食子酸酯(EGCG)，可以降低BMI-1水平，这种减少与皮肤癌细胞的增殖和存活减少有关。这些发现表明，化学预防药物可能通过降低BMI-1水平和活性来减少皮肤癌。关于化学预防药物可能通过干扰依赖于PcG基因的表观遗传调控机制发挥作用的想法尚未得到广泛的考虑或研究。这项建议的主要目标是了解EGCG如何调节皮肤癌中BMI-1的水平和活性。具体目标1中概述的研究旨在确定EGCG降低BMI-1水平和活性的机制(S)。在特定目标2中概述的实验旨在了解依赖EGCG的BMI-1水平的降低如何导致皮肤癌细胞存活率降低。特殊目的3集中于BMI-1多蛋白复合体中其他PcG基因产物的作用，特殊目的4利用表皮靶向BMI-1过表达模型检测BMI-1在体内的作用，以研究UVB依赖的皮肤癌变。公共卫生相关性多梳(PcG)蛋白通过表观遗传(染色质修饰)机制提高癌细胞的存活率。由于这一特性，PcG蛋白被认为是具有巨大潜力的抗癌治疗靶点。绿茶多酚是重要的饮食来源的癌症防御剂，可预防紫外线依赖型皮肤癌。我们的研究表明，绿茶中的一种活性物质减少了皮肤癌细胞中多梳基因的表达，使它们更容易受到细胞死亡的影响。我们的目标是确定抑制BMI-1PcG蛋白的水平和功能是否是绿茶多酚抑制紫外线依赖型皮肤癌发展的机制。这些研究被认为是创新的，因为化学预防药物对这一重要类型的表观遗传调控的影响以前没有被考虑进行研究。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE 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.