The Inhibitory Effect of (-)-Epigallocatechin-3-Gallate on Breast Cancer Progression via Reducing SCUBE2 Methylation and DNMT Activity
The Inhibitory Effect of (-)-Epigallocatechin-3-Gallate on Breast Cancer Progression via Reducing SCUBE2 Methylation and DNMT Activity
复制标题
(-)-表没食子儿茶素-3-没食子酸酯通过降低 SCUBE2 甲基化和 DNMT 活性对乳腺癌进展的抑制作用
DOI：
10.3390/molecules24162899
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发表时间：
2019-08-01
期刊：
影响因子：
4.6
通讯作者：
Xu, Yao
中科院分区：
文献类型：
--
作者：
Sheng, Jie;Shi, Weilin;Xu, Yao
表观遗传修饰是癌症进展的重要机制。越来越多的数据表明，(-)-表没食子儿茶素-3-没食子酸酯（EGCG），绿茶中最丰富的儿茶素，可能通过靶向表观遗传改变来阻止癌症的发生。我们发现信号肽- cub（补体蛋白C1r/C1s， Uegf和Bmp1）-EGF（表皮生长因子）结构域蛋白2 （SCUBE2）是一种肿瘤抑制基因，在乳腺肿瘤中被高甲基化。然而，EGCG是否调控SCUBE2甲基化尚不清楚，其机制也未明确。本研究旨在探讨EGCG对乳腺癌细胞中SCUBE2甲基化的影响。我们发现EGCG对细胞活力具有明显的抑制作用，并且具有剂量和时间依赖性，并且比其他儿茶素表现出更大的作用。EGCG处理导致SCUBE2基因增强，E-cadherin升高，vimentin表达降低，导致细胞迁移和侵袭受到明显抑制。EGCG对SCUBE2敲除细胞的抑制作用明显减轻。进一步研究表明，EGCG通过降低DNA甲基转移酶（DNMT）的表达和活性，显著降低SCUBE2的甲基化状态。综上所述，本研究首次报道了EGCG治疗可以逆转SCUBE2甲基化，最终抑制乳腺癌进展。这些结果提示EGCG的表观遗传作用及其在乳腺癌治疗中的潜在意义。
Epigenetic modifications are important mechanisms responsible for cancer progression. Accumulating data suggest that (-)-epigallocatechin-3-gallate (EGCG), the most abundant catechin of green tea, may hamper carcinogenesis by targeting epigenetic alterations. We found that signal peptide-CUB (complement protein C1r/C1s, Uegf, and Bmp1)-EGF (epidermal growth factor) domain-containing protein 2 (SCUBE2), a tumor suppressor gene, was hypermethylated in breast tumors. However, it is unknown whether EGCG regulates SCUBE2 methylation, and the mechanisms remain undefined. This study was designed to investigate the effect of EGCG on SCUBE2 methylation in breast cancer cells. We reveal that EGCG possesses a significantly inhibitory effect on cell viability in a dose- and time-dependent manner and presents more effects than other catechins. EGCG treatment resulted in enhancement of the SCUBE2 gene, along with elevated E-cadherin and decreased vimentin expression, leading to significant suppression of cell migration and invasion. The inhibitory effect of EGCG on SCUBE2 knock-down cells was remarkably alleviated. Further study demonstrated that EGCG significantly decreased the SCUBE2 methylation status by reducing DNA methyltransferase (DNMT) expression and activity. In summary, this study reported for the first time that SCUBE2 methylation can be reversed by EGCG treatment, finally resulting in the inhibition of breast cancer progression. These results suggest the epigenetic role of EGCG and its potential implication in breast cancer therapy.