Resveratrol modulates epigenetic regulators of promoter histone methylation and acetylation that restores BRCA1, p53, p21CIP1 in human breast cancer cell lines
Resveratrol modulates epigenetic regulators of promoter histone methylation and acetylation that restores BRCA1, p53, p21CIP1 in human breast cancer cell lines
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DOI：
10.1002/biof.1544
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发表时间：
2019-07-17
期刊：
影响因子：
6
通讯作者：
Kanade, Santosh R.
中科院分区：
文献类型：
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作者：
Chatterjee, Biji;Ghosh, Krishna;Kanade, Santosh R.
表观遗传酶催化组蛋白的翻译后修饰（PTMs），在染色质水平上决定基因表达的功能。白藜芦醇（RVT）是一种被广泛研究的抗癌天然分子，以恢复癌细胞中的BRCA1， p53和p21而闻名。我们的目的是研究组蛋白甲基化和乙酰化在这些肿瘤抑制基因上调中的作用。我们的研究结果表明，在20 μ M浓度下，RVT在MCF-7和MDA-MB-231乳腺癌细胞中显著增加BRCA1、p53和p21的表达，而降低蛋白精氨酸甲基转移酶5 （PRMT5）和Zeste同源物2增强子（EZH2）的表达48小时。H4R3me2s （PRMT5的催化产物）和H3K27me3 （PRMT5的催化产物）的总体损失。相比之下，RVT暴露导致赖氨酸去乙酰化酶（KDAC）活性和KDAC1-3的表达显著降低，而赖氨酸乙酰转移酶KAT2A/3B的表达与未暴露的细胞相比增加。结果，RVT增加了H3K9ac和H3K27ac标记的整体水平。染色质免疫沉淀显示，20 μ M RVT暴露显著降低了抑制组蛋白标记（H4R3me2s和H3K27me3）的富集，而BRCA1、p53和p21近端启动子区域内激活组蛋白标记（H3K9/27ac）的丰度增加。我们假设RVT通过影响甲基化和乙酰化酶的表达和功能来改变启动子组蛋白的表观遗传修饰，从而恢复这些至关重要的肿瘤抑制基因的表达。
The epigenetic enzymes catalyze posttranslational modifications (PTMs) of histones, which functionally determine gene expression at the chromatin level. Resveratrol (RVT) a much studied anti-cancer natural molecule is known for restoration of BRCA1, p53, and p21 in cancer cells. We aimed to investigate the role of histone methylation and acetylation on upregulation of these tumor suppressor genes. Our results suggest RVT significantly increase expression of BRCA1, p53, and p21, while decreased expression of protein arginine methyltransferase 5 (PRMT5) and enhancer of Zeste homolog 2 (EZH2) at a 20 mu M concentration by 48 hr in both MCF-7 and MDA-MB-231 breast cancer cells. Also, there was an overall loss of H4R3me2s (catalytic product of PRMT5) and H3K27me3 (catalytic product of PRMT5). In contrast, RVT exposure caused a significant decrease in lysine deacetylase (KDAC) activity and expression of KDAC1-3, whereas the expression of lysine acetyltransferase KAT2A/3B was increased compared to the unexposed cells. As an outcome, RVT increased global level of H3K9ac and H3K27ac marks. The chromatin immunoprecipitation showed 20 mu M RVT exposure significantly reduced the enrichment of repressive histone marks (H4R3me2s and H3K27me3) while the abundance of activating histone marks (H3K9/27ac) within the proximal promoter region of BRCA1, p53, and p21 was increased. We hypothesize RVT by affecting the expression and function of methylation and acetylation enzymes altered the epigenetic modifications on promoter histones that restored expression of these critically important tumor suppressor genes.