Genes Chromosomes & Cancer, 2014, 53(5):422-31.

Genistein Inhibits DNA Methylation and Increases Expression of Tumor Suppressor Genes in Human Breast Cancer Cells

Qi Xie, Qian Bai, Ling Yun Zou, et al

Department of Nutrition and Food Hygiene, Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, College of Military Preventive Medicine, Third Military Medical University, Chongqing, China

It has been previously demonstrated that genistein exhibits anticancer activity against breast cancer. However, the precise mechanisms underlying the anticancer effect of genistein, in particular the epigenetic basis, remain unclear. In this study, we investigated whether genistein could modulate the DNA methylation status and expression of cancer-related genes in breast cancer cells. We treated MCF-7 and MDA-MB-231 human breast cancer cells with genistein in vitro. We found that genistein decreased the levels of global DNA methylation, DNA methyltransferase (DNMT) activity and expression of DNMT1. Yet, the expression of DNMT3A and DNMT3B showed no significant change. Using molecular modeling, we observed that genistein might directly interact with the catalytic domain of DNMT1, thus competitively inhibiting the binding of hemimethylated DNA to the catalytic domain of DNMT1. Furthermore, genistein decreased DNA methylation in the promoter region of multiple tumor suppressor genes (TSGs) such as ataxia telangiectasia mutated (ATM), adenomatous polyposis coli (APC), phosphatase and tensin homolog (PTEN), mammary serpin peptidase inhibitor (SERPINB5), and increased the mRNA expression of these genes. However, we detected no significant changes in the DNA methylation status or mRNA expression of stratifin (SFN). These results suggest that the anticancer effect of genistein on breast cancer may be partly due to its ability to demethylate and reactivate methylation-silenced TSGs through direct interaction with the DNMT1 catalytic domain and inhibition of DNMT1 expression.

美国《基因染色体与癌症》，2014年5月

在人体乳腺癌细胞中金雀异黄素抑制 DNA 的甲基化并提高肿瘤抑制基因的表达

谢琦, 白浅，邹凌云，等

中国重庆市第三军医大学军事预防医学院营养与食品安全重点实验室营养和食品安全研究中心营养和食品安全部

先前已经证明金雀异黄素表现出对抗乳癌的抗癌活性。然而，金雀异黄素确切的抗癌作用机制，特别是表观遗传基础，目前仍不清楚。在此研究中，我们探究了在乳腺癌细胞中，金雀异黄素是否能调节 DNA的甲基化状态与癌症相关基因的表达。在体外我们用金雀异黄素处理 MCF-7 和 MDA-MB-231 人体乳腺癌细胞。我们发现，金雀异黄素降低了整体DNA 甲基化的水平、 DNA 甲基转移酶 (DNMT) 的活性以及 DNMT1的表达。然而，DNMT3A 和 DNMT3B 的表达没有表现出显著变化。使用分子建模，我们观察到金雀异黄素可能直接与 DNMT1的催化部位相互作用，从而竞争性地抑制半甲基化 的DNA 绑定到 DNMT1的催化部位。此外，在多肿瘤抑制基因 (Tsg)的启动子区，金雀异黄素降低 DNA的甲基化，例如共济失调毛细血管扩张症突变 (ATM)、 大肠息肉 (APC)、 磷酸酶和张力蛋白同源物 (PTEN)、 乳腺丝氨酸蛋白酶抑制剂多肽酶抑制剂 (SERPINB5)，并提高这些基因的 mRNA 表达。然而，我们在分层蛋白 (SFN)的DNA 甲基化状态或 mRNA 表达中检测到没有发生重大变化。这些结果表明，金雀异黄素对乳腺癌的抗癌作用可能部分由于其通过直接与 DNMT1 催化结构域相互作用导致脱甲基和重新激活甲基化静默TSGs的能力以及对 DNMT1 表达的抑制能力。