title: Epigenetic modification of Nrf2 in 5-fluorouracil-resistant colon cancer cells: involvement of TET-dependent DNA demethylation.
abstract: 5-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.
authors.affiliation: School of Medicine, Jeju National University, Jeju, Korea.
authors.forename: K A
authors.initials: KA
authors.lastname: Kang
authors.affiliation: School of Medicine, Jeju National University, Jeju, Korea.
authors.forename: M J
authors.initials: MJ
authors.lastname: Piao
authors.affiliation: School of Medicine, Jeju National University, Jeju, Korea.
authors.forename: K C
authors.initials: KC
authors.lastname: Kim
authors.affiliation: School of Medicine, Jeju National University, Jeju, Korea.
authors.forename: H K
authors.initials: HK
authors.lastname: Kang
authors.affiliation: School of Medicine, Jeju National University, Jeju, Korea.
authors.forename: W Y
authors.initials: WY
authors.lastname: Chang
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: I C
authors.initials: IC
authors.lastname: Park
authors.affiliation: Department of Biochemistry, College of Pharmacy, Dongguk University, Goyang, Korea.
authors.forename: Y S
authors.initials: YS
authors.lastname: Keum
authors.affiliation: Tumor Microenvironment Global Core Research Center and Cancer Research Institute, Seoul National University, Seoul, Korea.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Surh
authors.affiliation: School of Medicine, Jeju National University, Jeju, Korea.
authors.forename: J W
authors.initials: JW
authors.lastname: Hyun
mesh_terms: D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005472:Fluorouracil / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008819:Mice, Nude; D006899:Mixed Function Oxygenases; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D051267:NF-E2-Related Factor 2; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; D051547:Heme Oxygenase-1; D004248:DNA (Cytosine-5-)-Methyltransferases; D005472:Fluorouracil
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