Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008, India.
Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008, India.
Biochim Biophys Acta Mol Basis Dis. 2019 Jun 1;1865(6):1651-1665. doi: 10.1016/j.bbadis.2019.04.002. Epub 2019 Apr 4.
Loss of E-cadherin and epithelial to mesenchymal transition (EMT) are key steps in cancer progression. Reactive oxygen species (ROS) play significant roles in cellular physiology and homeostasis. Roles of E-cadherin (CDH1), EMT and ROS are intriguingly illustrated in many cancers without focusing their collective concert during cancer progression. We report that hydrogen peroxide (HO) treatment modulate CDH1 gene expression by epigenetic modification(s). Sublethal dosage of HO treatment decrease E-cadherin, increase DNMT1, HDAC1, Snail, Slug and enrich H3K9me3 and H3K27me3 in the CDH1 promoter. The effect of HO was attenuated by ROS scavengers; NAC, lupeol and beta-sitosterol. DNMT inhibitor, AZA prevented the HO induced promoter-CpG-island methylation of CDH1. Treatment of cells with U0126 (inhibitor of ERK) reduced the expression of DNMT1, Snail and Slug, increased CDH1. This implicates that CDH1 is synergistically repressed by histone methylation, DNA methylation and histone deacetylation mediated chromatin remodelling and activation of Snail and Slug through ERK pathway. Increased ROS leads to activation of epigenetic machineries and EMT activators Snail/Slug which in their course of action inactivates CDH1 gene and lack of E-cadherin protein promotes EMT in breast cancer cells. ROS and ERK signaling facilitate epigenetic silencing and support the fact that subtle increase of ROS above basal level act as key cell signaling molecules. Free radical scavengers, lupeol and beta-sitosterol may be tested for therapeutic intervention of breast cancer. This work broadens the amplitude of epigenome and open avenues for investigations on conjoint effects of canonical and intrinsic metabolite signaling and epigenetic modulations in cancer.
E-钙黏蛋白的丢失和上皮-间充质转化（EMT）是癌症进展的关键步骤。活性氧（ROS）在细胞生理和动态平衡中发挥着重要作用。E-钙黏蛋白（CDH1）、EMT 和 ROS 的作用在许多癌症中得到了很好的说明，而没有集中在癌症进展过程中的集体协同作用。我们报告过氧化氢（HO）处理通过表观遗传修饰（s）调节 CDH1 基因表达。亚致死剂量的 HO 处理降低 E-钙黏蛋白，增加 DNMT1、HDAC1、Snail、Slug，并在 CDH1 启动子中富集 H3K9me3 和 H3K27me3。HO 的作用被 ROS 清除剂减弱；NAC、羽扇豆醇和β-谷甾醇。DNMT 抑制剂 AZA 可防止 HO 诱导的 CDH1 启动子-CpG 岛甲基化。用 U0126（ERK 抑制剂）处理细胞可降低 DNMT1、Snail 和 Slug 的表达，增加 CDH1。这表明 CDH1 被组蛋白甲基化、DNA 甲基化和组蛋白去乙酰化介导的染色质重塑以及通过 ERK 通路激活 Snail 和 Slug 协同抑制。ROS 的增加导致表观遗传机制和 EMT 激活物 Snail/Slug 的激活，在其作用过程中，CDH1 基因失活，E-钙黏蛋白蛋白缺失促进乳腺癌细胞的 EMT。ROS 和 ERK 信号促进表观遗传沉默，并支持这样一个事实，即在基础水平之上，ROS 的微小增加充当关键的细胞信号分子。自由基清除剂羽扇豆醇和β-谷甾醇可能被测试用于乳腺癌的治疗干预。这项工作拓宽了表观基因组的幅度，并为研究经典和内在代谢物信号与癌症中的表观遗传调节的联合效应开辟了途径。
