期刊
BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE
卷 85, 期 3, 页码 337-346出版社
CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS
DOI: 10.1139/O07-009
关键词
DPYD; dihydropyrinfidine dehydrogenase; promoter; DNA methylation; colorectal cancer RKO cell line
资金
- NCI NIH HHS [CA62164] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA062164] Funding Source: NIH RePORTER
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 Spl, 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.
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