PDF(Pubmed)
Abstract：
ST08 and ST09 are potent curcumin derivatives with antiproliferative, apoptotic, and migrastatic properties. Both ST08 and ST09 exhibit in vitro and in vivo anticancer properties. As reported earlier, these derivatives were highly cytotoxic towards MDA-MB-231 triple-negative breast cancer cells with IC50 values in the nanomolar (40-80nM) range.In this study,we performed whole-genome bisulfite sequencing(WGBS) of untreated (control), ST08 and ST09 (treated) triple-negative breast cancer cell line MDA-MB-231 to unravel epigenetic changes induced by the drug. We identified differentially methylated sites (DMSs) enriched in promoter regions across the genome. Analysis of the CpG island promoter methylation identified 12 genes common to both drugs, and 50% of them are known to be methylated in patient samples that were hypomethylated by drugs belonging to the homeobox family transcription factors.Methylation analysis of the gene body revealed 910 and 952 genes to be hypermethylatedin ST08 and ST09 treated MDA-MB-231 cells respectively. Correlation of the gene body hypermethylation with expression revealed CACNAH1 to be upregulated in ST08 treatment and CDH23 upregulation in ST09.Further, integrated analysis of the WGBS with RNA-seq identified uniquely altered pathways - ST08 altered ECM pathway, and ST09 cell cycle, indicating drug-specific signatures.
摘要：
ST08和ST09是具有抗增殖作用的有效姜黄素衍生物，凋亡，和杂乱属性。ST08和ST09均表现出体外和体内抗癌特性。如前所述，这些衍生物对MDA-MB-231三阴性乳腺癌细胞具有高度细胞毒性,IC50值在纳摩尔(40-80nM)范围内.在这项研究中,我们对未处理的（对照）进行了全基因组亚硫酸氢盐测序（WGBS），ST08和ST09（治疗）三阴性乳腺癌细胞系MDA-MB-231，以解开药物诱导的表观遗传变化。我们确定了基因组中启动子区域富集的差异甲基化位点(DMS)。CpG岛启动子甲基化分析确定了两种药物共有的12个基因，已知其中50％在患者样品中被甲基化，这些样品被属于同源盒家族转录因子的药物低甲基化。基因体的甲基化分析显示，在ST08和ST09处理的MDA-MB-231细胞中，分别有910和952个基因是高甲基化的。基因体高甲基化与表达的相关性显示，CACNAH1在ST08治疗中上调，CDH23在ST09中上调。Further,WGBS与RNA-seq的综合分析鉴定出独特改变的途径-ST08改变的ECM途径，和ST09细胞周期，表明药物特异性特征。
