Promoter demethylation of nuclear factor-erythroid 2-related factor 2 gene in drug-resistant colon cancer cells

Zhao,Xiao‑Qian; Zhang,Yi‑Fei; Xia,Yi‑Fang; Zhou,Zhong‑Mei; Cao,Ying‑Qing

doi:10.3892/ol.2015.3468

Promoter demethylation of nuclear factor-erythroid 2-related factor 2 gene in drug-resistant colon cancer cells

Authors:
- Xiao‑Qian Zhao
- Yi‑Fei Zhang
- Yi‑Fang Xia
- Zhong‑Mei Zhou
- Ying‑Qing Cao
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Affiliations: Department of Digestive Diseases, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China, Department of Gastrointestinal Surgery, Yantai Yuhuangding Hospital Affiliated to Medical College of Qingdao University, Yantai, Shandong 264000, P.R. China, Department of Medical Imaging, The Sixth People's Hospital of Jinan City, Jinan, Shandong 250200, P.R. China, Department of Child Medicine, Taian Central Hospital, Taian, Shandong 271000, P.R. China, Department of Anorectal Surgery, Taian Central Hospital, Taian, Shandong 271000, P.R. China
Published online on: July 8, 2015 https://doi.org/10.3892/ol.2015.3468
Pages: 1287-1292
Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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.

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