Suppression of DPYD expression in RKO Cells via DNA methylation in the regulatory region of the DPYD promoter: a potentially important epigenetic mechanism regulating DPYD expression

Author:

Zhang Xue1234,Soong Richie1234,Wang Kangsheng1234,Li Lin1234,Davie James R.1234,Guarcello Vincenzo1234,Diasio Robert B.1234

Affiliation:

1. Mayo Clinic Cancer Center, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905, USA.

2. Oncology Research Institute, National University of Singapore, Republic of Singapore.

3. Department of Pharmacology and Toxicology, University of AL at Birmingham, Birmingham, AL 35294, USA.

4. MB Institute of Cell Biology, University of Manitoba, Winnipeg, MB R3E 0V9, Canada.

Abstract

Dihydropyrimidine dehydrogenase (DPD) is one of the factors that determine the efficacy and toxicity of 5-fluorouracil. Variations in DPD activity may result from alterations at the transcriptional level of the DPYD gene. Heterogeneity in DPYD expression has been reported, but the molecular mechanisms responsible for this remain unclear. We investigated methylation of the DPYD promoter as a mechanism for transcriptional regulation of DPYD in the RKO colorectal cancer cell line. We demonstrate that the active transcription machinery for DPYD is present in RKO cells, but promoter binding of Sp1, a transactivator of DPYD, was inhibited, which on subsequent examination was shown to be associated with dense promoter methylation. Treatment with 5-aza-2′-deoxycytidine alone or the combination of 5-aza-2′-deoxycytidine and trichostatin A induced demethylation of the promoter and markedly increased the DPYD mRNA level in RKO cells but not in unmethylated WiDr cells. Furthermore, in vitro methylation of the DPYD promoter decreased promoter activity. These data suggest an important role for methylation in DPYD suppression. The transcriptional suppression of DPYD by methylation may be responsible for the increased 5-fluorouracil sensitivity observed in some patients. This may also provide insight into the mechanism underlying the downregulation of DPYD in some colorectal cancers.

Publisher

Canadian Science Publishing

Subject

Cell Biology,Molecular Biology,Biochemistry

Cited by 19 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3