The Bmi-1 polycomb protein antagonizes the (-)-epigallocatechin-3-gallate-dependent suppression of skin cancer cell survival
The Bmi-1 polycomb protein antagonizes the (-)-epigallocatechin-3-gallate-dependent suppression of skin cancer cell survival
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DOI：
10.1093/carcin/bgp314
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发表时间：
2010-03-01
期刊：
影响因子：
4.7
通讯作者：
Eckert, Richard L.
中科院分区：
文献类型：
--
作者：
Balasubramanian, Sivaprakasam;Adhikary, Gautam;Eckert, Richard L.
多梳组（PcG）蛋白是增强细胞存活的基因表达的表观遗传调节剂。这种调节通过两种多蛋白PcG复合物PRC 2（EED）和PRC 1 [B细胞特异性莫洛尼鼠白血病病毒整合位点1（Bmi-1）]的作用来实现。这些复合物通过增加组蛋白甲基化和减少乙酰化来调节基因表达，从而形成封闭的染色质构象。这些蛋白质的活性与增加的细胞增殖和存活相关。我们发现在永生化角质形成细胞和皮肤癌细胞系中关键PcG蛋白的表达增加。我们研究了两个关键的PcG蛋白，Bmi-1和增强子的zeste同系物2（EZH 2）的作用，和活性剂的影响，在绿色茶，（-）-表没食子儿茶素-3-没食子酸酯（EGCG），对这些监管机构的功能。EGCG处理SCC-13细胞降低Bmi-1和Ezh 2水平，这与细胞存活率降低有关。存活率的降低与组蛋白H3赖氨酸27三甲基化的整体降低相关，这是PRC 2复合物作用的标志。PcG蛋白表达的这种变化与增强细胞周期进展的关键蛋白[细胞周期蛋白依赖性激酶（cdk）1、cdk 2、cdk 4、细胞周期蛋白D1、细胞周期蛋白E、细胞周期蛋白A和细胞周期蛋白B1]的表达减少和抑制细胞周期进展的蛋白（p21和p27）的表达增加有关。细胞凋亡也被增强，如通过增加的半胱天冬酶9、8和3切割和增加的聚（腺苷二磷酸核糖）聚合酶切割所证明的。EGCG处理还增加Bax并抑制Bcl-xL表达。载体介导的增强Bmi-1表达逆转这些EGCG依赖性变化。这些发现表明，绿色茶多酚通过影响PcG介导的表观遗传调节机制来降低皮肤肿瘤细胞的存活率。
The polycomb group (PcG) proteins are epigenetic regulators of gene expression that enhance cell survival. This regulation is achieved via action of two multiprotein PcG complexes-PRC2 (EED) and PRC1 [B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1)]. These complexes modulate gene expression by increasing histone methylation and reducing acetylation-leading to a closed chromatin conformation. Activity of these proteins is associated with increased cell proliferation and survival. We show increased expression of key PcG proteins in immortalized keratinocytes and skin cancer cell lines. We examine the role of two key PcG proteins, Bmi-1 and enhancer of zeste homolog 2 (Ezh2), and the impact of the active agent in green tea, (-)-epigallocatechin-3-gallate (EGCG), on the function of these regulators. EGCG treatment of SCC-13 cells reduces Bmi-1 and Ezh2 level and this is associated with reduced cell survival. The reduction in survival is associated with a global reduction in histone H3 lysine 27 trimethylation, a hallmark of PRC2 complex action. This change in PcG protein expression is associated with reduced expression of key proteins that enhance progression through the cell cycle [cyclin-dependent kinase (cdk)1, cdk2, cdk4, cyclin D1, cyclin E, cyclin A and cyclin B1] and increased expression of proteins that inhibit cell cycle progression (p21 and p27). Apoptosis is also enhanced, as evidenced by increased caspase 9, 8 and 3 cleavage and increased poly(adenosine diphosphate ribose) polymerase cleavage. EGCG treatment also increases Bax and suppresses Bcl-xL expression. Vector-mediated enhanced Bmi-1 expression reverses these EGCG-dependent changes. These findings suggest that green tea polyphenols reduce skin tumor cell survival by influencing PcG-mediated epigenetic regulatory mechanisms.