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

被引:45
作者
El-Khoury, V. [1 ]
Breuzard, G. [1 ]
Fourre, N. [1 ]
Dufer, J. [1 ]
机构
[1] Univ Reims, Unite MeDIAN CNRS, UMR 6142, Fac Pharm,IFR 53, F-51096 Reims, France
关键词
trichostatin A; epigenetics; drug resistance;
D O I
10.1038/sj.bjc.6603914
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Tumour drug-resistant ABCBI gene expression is regulated at the chromatin level through epigenetic mechanisms. We examined the effects of the histone deacetylase inhibitor trichostatin A (TSA) on ABCBI gene expression in small cell lung carcinoma (SCLC) drug-sensitive (H69WT) or etoposide-resistant (H69VP) cells. We found that TSA induced an increase in ABCBI 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 ABCBI 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. ABCBI 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 MBDI binding to the ABCBI 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 ABCBI expression through a transcriptional mechanism, independently of promoter methylation, and MBD1 or PCAF recruitment.
引用
收藏
页码:562 / 573
页数:12
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