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

• DOI: 10.1038/cddis.2014.149
• Publication Date: 2014-04-17T15:01:13Z
• Authors: K A Kang; M J Piao; K C Kim; H K Kang; W Y Chang; I C Park; Y S Keum; Y J Surh; J W Hyun
• Keywords: DNA demethylation; Viability assay

5-Fluorouracil (5-FU) is a widely used anticancer drug for the treatment of colorectal cancer (CRC). However, resistance to 5-FU often prevents success chemotherapy. Nuclear factor-erythroid 2-related factor 2 (Nrf2) transcriptional regulator and possible target overcome resistance. The present study examined epigenetic changes associated with Nrf2 induction in human CRC cell line (SNUC5) resistant (SNUC5/5-FUR). expression, nuclear translocation, binding promoter were higher SNUC5/5-FUR cells than SNUC5 cells. activated led an increase protein expression activity heme oxygenase-1 (HO-1), Nrf2-regulated gene. produced larger amount reactive oxygen species (ROS) siRNA- or shRNA-mediated knockdown HO-1 significantly suppressed viability tumor growth vitro vivo, resulting enhanced sensitivity. Methylation-specific (MS) real-time quantitative MS-PCR data showed hypomethylation CpG islands compared Expression DNA demethylase ten-eleven translocation (TET) was upregulated ROS generated by TET1 function, whereas antioxidant had opposite effect. These results suggested that mechanism underlying acquisition involves upregulation via modifications demethylation.