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Epigenetic modification of Nrf2 in 5-fluorouracil-resistant colon cancer cells: Involvement of TET-dependent DNA demethylation

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dc.contributor.authorKang, K. A.-
dc.contributor.authorPiao, M. J.-
dc.contributor.authorKim, K. C.-
dc.contributor.authorKang, H. K.-
dc.contributor.authorChang, W. Y.-
dc.contributor.authorPark, I. C.-
dc.contributor.authorKeum, Y. S.-
dc.contributor.authorSurh, Young-Joon-
dc.contributor.authorHyun, J. W.-
dc.date.accessioned2021-01-31T09:25:25Z-
dc.date.available2021-01-31T09:25:25Z-
dc.date.issued2014-04-
dc.identifier.citationCell Death and Disease, Vol.5 No.4, p. e1183-
dc.identifier.issn2041-4889-
dc.identifier.other85270-
dc.identifier.urihttps://hdl.handle.net/10371/172662-
dc.description.abstract5-Fluorouracil (5-FU) is a widely used anticancer drug for the treatment of colorectal cancer (CRC). However, resistance to 5-FU often prevents the success of chemotherapy. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a transcriptional regulator and a possible target to overcome 5-FU resistance. The present study examined epigenetic changes associated with Nrf2 induction in a human CRC cell line (SNUC5) resistant to 5-FU (SNUC5/5-FUR). Nrf2 expression, nuclear translocation, and binding to promoter were higher in SNUC5/5-FUR cells than in SNUC5 cells. The activated Nrf2 in SNUC5/5-FUR cells led to an increase in the protein expression and activity of heme oxygenase-1 (HO-1), an Nrf2-regulated gene. SNUC5/5-FUR cells produced a larger amount of reactive oxygen species (ROS) than SNUC5 cells. The siRNA-or shRNA-mediated knockdown of Nrf2 or HO-1 significantly suppressed cancer cell viability and tumor growth in vitro and in vivo, resulting in enhanced 5-FU sensitivity. Methylation-specific (MS) or real-time quantitative MS-PCR data showed hypomethylation of the Nrf2 promoter CpG islands in SNUC5/5-FUR cells compared with SNUC5 cells. Expression of the DNA demethylase ten-eleven translocation (TET) was upregulated in SNUC5/5-FUR cells. ROS generated by 5-FU upregulated TET1 expression and function, whereas antioxidant had the opposite effect. These results suggested that the mechanism underlying the acquisition of 5-FU resistance in CRC involves the upregulation of Nrf2 and HO-1 expression via epigenetic modifications of DNA demethylation.-
dc.subjectcolon cancer cells-
dc.subject5-fluorouracil resistance-
dc.subjectepigenetic modification-
dc.subjectDNA demethylase-
dc.subjectNrf2-
dc.subjectoxidative stress-
dc.titleEpigenetic modification of Nrf2 in 5-fluorouracil-resistant colon cancer cells: Involvement of TET-dependent DNA demethylation-
dc.typeArticle-
dc.contributor.AlternativeAuthor서영준-
dc.identifier.doi10.1038/cddis.2014.149-
dc.citation.journaltitleCell Death and Disease-
dc.identifier.scopusid2-s2.0-84901018671-
dc.citation.number4-
dc.citation.startpagee1183-
dc.citation.volume5-
dc.identifier.urlhttps://www.nature.com/articles/cddis2014149-
dc.identifier.rimsid85270-
dc.identifier.sci000335450400029-
dc.contributor.affiliatedAuthorSurh, Young-Joon-
Appears in Collections:
Graduate School of Convergence Science and Technology (융합과학기술대학원)Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과)Journal Papers (저널논문_분자의학 및 바이오제약학과)
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