Bmi-1 and Skin Cancer Prevention

摘要 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的。多梳群(PcG)基因 编码一组重要的细胞存活蛋白，最初被发现用于增强干细胞 生死存亡。这些蛋白质通过全球表观遗传(染色质修饰)机制抑制基因 表达并提高细胞存活率。它们是关键的表观遗传控制者。因为它们能促进细胞 增殖和存活，并通过表观遗传机制运作，PcG蛋白被认为具有 作为抗癌治疗靶点的潜力巨大。尽管PcG基因在人类基因组中具有潜在的重要性 提高癌细胞存活率，饮食衍生的化学预防药物在调节其功能中的作用 还没有得到解决。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在皮肤癌细胞和 BMI-1的靶向过表达可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)， 降低BMI-1水平，这种减少与皮肤癌细胞增殖减少和 生死存亡。这些发现表明，化学预防药物可能通过减少皮肤癌 BMI-1水平和活性。认为化学预防药物可能通过干扰PcG基因发挥作用的想法- 依赖的表观遗传调控机制尚未被广泛考虑或研究。主要目标是 这项建议的目的是了解EGCG如何调节皮肤癌中BMI-1的水平和活性。这个 具体目标1中概述的研究旨在确定EGCG减少的机制(S BMI-1水平和活性。《特定目标2》中概述的实验旨在了解 依赖于EGCG的BMI-1水平的降低导致皮肤癌细胞存活率降低。具体目标3 重点关注作为BMI-1多蛋白复合体一部分的其他PcG基因产物的贡献， 特定目标4利用表皮靶向的BMI-1过表达来检测BMI-1在体内的作用 建立中波紫外线依赖的皮肤癌模型。叙述性 多梳(PcG)蛋白通过表观遗传(染色质修饰)机制增强癌症 细胞存活。由于这一特性，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可以减少杂物。 皮肤癌细胞中的基因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-1 PcG蛋白的水平和功能是否是绿茶 多酚可抑制紫外线依赖型皮肤癌的发展。这些研究被认为是 因为化学预防药物对这种重要类型的表观遗传学的影响是创新的 此前还没有考虑对监管进行研究。

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.