Cytostatic drug treatment causes seeding of gene promoter methylation

被引:17
作者
Bredberg, Anders
Bodmer, Walter [1 ]
机构
[1] John Radcliffe Hosp, Canc Res UK Canc & Immunogenet Lab, Weatherall Inst Mol Med, Oxford OX3 9DS, England
[2] Lund Univ, Dept Med Microbiol, Malmo Univ Hosp, S-20520 Malmo, Sweden
关键词
DNA methylation; drug resistance; 6-thioguanine; colorectal cancer; HPRT;
D O I
10.1016/j.ejca.2006.12.003
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Epigenetic changes in multiple genes are emerging as an important mechanism for tumour cells to acquire resistance to chemotherapy. In the present work, we test the hypothesis that epigenetic Organisation in cancer cells can be affected by cytostatic drugs. Colorectal cancer cells were cultured for several weeks in the presence of 6-thioguanine. Bisulphite sequencing of the CpG-rich promoter regions of two expressed genes showed a significantly increased frequency of methylated CpG sites in drug-treated cells, as compared with controls: 4.7% and 1.7%, respectively, for the HPRT gene; and 11.1% and 8.2% for CDX1. Essentially, all of the increase for the CDX1 gene was in a four CpG sub-region previously found to correlate with gene activity (P = 0.006). This pattern of sparse promoter methylation fits with a recently proposed 'seeding' two-step mechanism leading up to gene inactivation in cancer cells. Taken together, our findings suggest activation in cancer cells of an epigenetic process enabling a tumour to generate drug-resistant variant cells. (c) 2006 Elsevier Ltd. All rights reserved.
引用
收藏
页码:947 / 954
页数:8
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