Promoter demethylation of nuclear factor-erythroid 2-related factor 2 gene in drug-resistant colon cancer cells
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作者单位
摘要
The mechanisms underlying drug resistance in colorectal cancer (CRC) treatment remain to be fully elucidated. Therefore, the present study aimed to investigate the underlying mechanism resistance to a widely used anticancer drug, 5-Fluorouracil (5-FU). Nuclear factor-erythroid 2-related factor 2 (Nrf2) is an important transcription factor involved in cellular protection. In the present study, it was hypothesized that the epigenetic modification of Nrf2 may be a potential target for 5-FU resistance in CRC treatment. Protein and messenger RNA levels of Nrf2, heme oxygenase-1 (HO-1), DNA methylases and DNA methyltransferases were determined and DNA methylation analysis for the Nrf2 promoter was performed in a human CRC control (SNU-C5) and resistant (SNU-C5R) cell line. The results demonstrated that Nrf2 expression levels, nuclear translocation and promoter binding were significantly increased in SNU-C5R cells compared with SNU-C5 cells. Elevated levels of activated Nrf2 in SNU-C5R cells resulted in the increased protein expression and activity of HO-1. In addition, increased production of reactive oxygen species (ROS) and upregulation of ten-eleven translocation (TET) 1 were observed in SNU-C5R cells compared with SNU-C5 cells. Furthermore, methylation analysis revealed Nrf2 promoter cytosine-phosphate-guanine island hypomethylation in 5-FU-treated cells. In conclusion, the results indicated that 5-FU-induced ROS production resulted in the upregulation of TET1 expression and function. In addition, these results indicated that TET-dependent demethylation of the Nrf2 promoter upregulated Nrf2 and HO-1 expression, which induced cellular protection mechanisms, ultimately leading to drug resistance.
关键词
COLORECTAL-CANCER; HEME OXYGENASE-1; TET PROTEINS; KEAP1; NRF2; 5-FLUOROURACIL; IDENTIFICATION; CHEMOTHERAPY; ACTIVATION; EXPRESSION
基本信息
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所属机构:保健消化内科
归属医师: 赵小茜
UT:000360923000011
刊名:ONCOLOGY LETTERS
年,卷(期):2015年10卷3期
页码:1287-1292
DOI:10.3892/ol.2015.3468
附件:
收录: SCIE