The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription-dependent mechanism in a drug-resistant small cell lung carcinoma cell line model.
The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription-dependent mechanism in a drug-resistant small cell lung carcinoma cell line model.
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DOI：
10.1038/sj.bjc.6603914
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发表时间：
2007-08-20
影响因子：
8.8
通讯作者：
Dufer, J.
中科院分区：
文献类型：
--
作者：
El-Khoury, V.;Breuzard, G.;Fourre, N.;Dufer, J.
肿瘤耐药 ABCB1 基因表达通过表观遗传机制在染色质水平上受到调节。我们研究了组蛋白脱乙酰酶抑制剂曲古抑菌素 A (TSA) 对小细胞肺癌 (SCLC) 药物敏感 (H69WT) 或依托泊苷耐药 (H69VP) 细胞中 ABCB1 基因表达的影响。我们发现 TSA 诱导药物敏感细胞中 ABCB1 表达增加，但在耐药细胞中强烈降低 ABCB1 表达。这些上调和下调发生在转录水平。蛋白质合成抑制减少了这些调节，但并没有完全抑制它们。在 ABCB1 启动子处观察到组蛋白乙酰化的差异时间模式：两种细胞系中 H4 乙酰化均增加，但 H3 乙酰化不同，H69WT 细胞中逐渐增加，但 H69VP 细胞中短暂增加。 ABCB1调控与启动子-50GC、-110GC和Inr位点的甲基化状态无关，并且不会导致这些甲基化谱的进一步变化。曲古抑菌素 A 处理不会改变 MBD1 与 ABCB1 启动子的结合，并且类似地增加两种 H69 细胞系中 PCAF 的结合。我们的结果表明，在 H69 耐药 SCLC 细胞系中，TSA 通过转录机制诱导 ABCB1 表达下调，与启动子甲基化和 MBD1 或 PCAF 募集无关。
Tumour drug-resistant ABCB1 gene expression is regulated at the chromatin level through epigenetic mechanisms. We examined the effects of the histone deacetylase inhibitor trichostatin A (TSA) on ABCB1 gene expression in small cell lung carcinoma (SCLC) drug-sensitive (H69WT) or etoposide-resistant (H69VP) cells. We found that TSA induced an increase in ABCB1 expression in drug-sensitive cells, but strongly decreased it in drug-resistant cells. These up- and downregulations occurred at the transcriptional level. Protein synthesis inhibition reduced these modulations, but did not completely suppress them. Differential temporal patterns of histone acetylation were observed at the ABCB1 promoter: increase in H4 acetylation in both cell lines, but different H3 acetylation with a progressive increase in H69WT cells but a transient one in H69VP cells. ABCB1 regulations were not related with the methylation status of the promoter −50GC, −110GC, and Inr sites, and did not result in further changes to these methylation profiles. Trichostatin A treatment did not modify MBD1 binding to the ABCB1 promoter and similarly increased PCAF binding in both H69 cell lines. Our results suggest that in H69 drug-resistant SCLC cell line TSA induces downregulation of ABCB1 expression through a transcriptional mechanism, independently of promoter methylation, and MBD1 or PCAF recruitment.
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