Histone Deacetylase-1-mediated Suppression of FAS in Chemoresistant Ovarian Cancer Cells.
Histone Deacetylase-1-mediated Suppression of FAS in Chemoresistant Ovarian Cancer Cells.
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作者：
E. Cacan
背景卵巢癌细胞中FAS表达的缺失最近被认为与化疗药物的耐药性有关。然而，抑制FAS表达的机制尚不清楚。材料与方法采用流式细胞术和实时定量聚合酶链反应分别检测卵巢癌亲本化疗敏感细胞（A2780）及其衍生的化疗耐药细胞（A2780-AD）的细胞表面和转录本死亡受体的表达。通过染色质免疫沉淀法测定FAS启动子在A2780和A2780-AD卵巢上皮细胞中的表观遗传调控。结论A2780-AD细胞中FAS的表达受到抑制。与亲本细胞相比，在A2780-AD细胞之间的FAS启动子处未观察到DNA甲基化差异。然而，与亲本细胞相比，A2780-AD细胞中与FAS启动子相关的乙酰化组蛋白H3的水平显著降低，并且在抗性细胞中与FAS启动子相关的组蛋白脱乙酰酶1（HDAC 1）酶相应增加。HDAC 1表达的敲低和HDAC酶活性的药理学抑制显著增加了耐药A2780-AD细胞中FAS的表达。这些结果表明，组蛋白修饰的表观遗传变化可能导致FAS表达在化疗耐药的卵巢癌细胞中的损失，并且FAS表达的增强可以增加肿瘤细胞对免疫细胞的敏感性。
BACKGROUND Loss of FAS expression in ovarian cancer cells has recently been associated with resistance to chemotherapeutic drugs. However, the mechanism for suppression of FAS expression is unknown. MATERIALS AND METHODS The cell surface and transcript expressions of death receptors in parental chemosensitive (A2780) and their derivative chemoresistant (A2780-AD) ovarian cancer cells were determined by flow cytometry and quantitative real-time polymerase chain reaction, respectively. The epigenetic regulation of FAS promoters in both A2780 and A2780-AD ovarian epithelial cells were determined by chromatin immunoprecipitation assays. CONCLUSION This study demonstrated that expression of FAS is suppressed in A2780-AD cells compared to parental A2780 ovarian cells. No difference in DNA methylation was observed at FAS promoters between A2780-AD cells compared to parental cells. However, the level of acetylated histone H3 associated with FAS promoter in A2780-AD cells was significantly lower compared to parental cells, and there was a corresponding increase in histone deacetylase 1 (HDAC1) enzyme associated with the FAS promoter in resistant cells. Knockdown of HDAC1 expression, and pharmacological inhibition of HDAC enzymatic activity significantly increased FAS expression in resistant A2780-AD cells. These results suggest that epigenetic changes in histone modifications may contribute to the loss of FAS expression in chemoresistant ovarian cancer cells and that enhancement of FAS expression could increase tumor cell sensitivity to immune cells.