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Epigenetic modification of Nrf2 in 5-fluorouracil-resistant colon cancer cells: involvement of TET-dependent DNA demethylation.
Kang, K A; Piao, M J; Kim, K C; Kang, H K; Chang, W Y; Park, I C; Keum, Y S; Surh, Y J; Hyun, J W.
Afiliación
  • Kang KA; School of Medicine, Jeju National University, Jeju, Korea.
  • Piao MJ; School of Medicine, Jeju National University, Jeju, Korea.
  • Kim KC; School of Medicine, Jeju National University, Jeju, Korea.
  • Kang HK; School of Medicine, Jeju National University, Jeju, Korea.
  • Chang WY; School of Medicine, Jeju National University, Jeju, Korea.
  • Park IC; Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
  • Keum YS; Department of Biochemistry, College of Pharmacy, Dongguk University, Goyang, Korea.
  • Surh YJ; Tumor Microenvironment Global Core Research Center and Cancer Research Institute, Seoul National University, Seoul, Korea.
  • Hyun JW; School of Medicine, Jeju National University, Jeju, Korea.
Cell Death Dis ; 5: e1183, 2014 Apr 17.
Article en En | MEDLINE | ID: mdl-24743738
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Proto-Oncogénicas / Neoplasias del Colon / Resistencia a Antineoplásicos / Metilación de ADN / Epigénesis Genética / Proteínas de Unión al ADN / Factor 2 Relacionado con NF-E2 / Fluorouracilo Límite: Animals / Humans Idioma: En Revista: Cell Death Dis Año: 2014 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Proto-Oncogénicas / Neoplasias del Colon / Resistencia a Antineoplásicos / Metilación de ADN / Epigénesis Genética / Proteínas de Unión al ADN / Factor 2 Relacionado con NF-E2 / Fluorouracilo Límite: Animals / Humans Idioma: En Revista: Cell Death Dis Año: 2014 Tipo del documento: Article Pais de publicación: Reino Unido