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

被引：117

作者：

Kang, K. A. ^{[1
]}

Piao, M. J. ^{[1
]}

Kim, K. C. ^{[1
]}

Kang, H. K. ^{[1
]}

Chang, W. Y. ^{[1
]}

Park, I. C. ^{[2
]}

Keum, Y. S. ^{[3
]}

Surh, Y. J. ^{[4
,5
]}

Hyun, J. W. ^{[1
]}

机构：

[1] Jeju Natl Univ, Sch Med, Cheju 690756, South Korea

[2] Korea Inst Radiol & Med Sci, Div Radiat Canc Res, Seoul, South Korea

[3] Dongguk Univ, Coll Pharm, Dept Biochem, Goyang, South Korea

[4] Seoul Natl Univ, Tumor Microenvironment Global Core Res Ctr, Seoul, South Korea

[5] Seoul Natl Univ, Canc Res Inst, Seoul, South Korea

来源：

CELL DEATH & DISEASE | 2014年 / 5卷

关键词：

colon cancer cells; 5-fluorouracil resistance; epigenetic modification; DNA demethylase; Nrf2; oxidative stress; HEME OXYGENASE-1; COLORECTAL-CANCER; DRUG-RESISTANCE; GENE-EXPRESSION; PROTEINS; MECHANISMS; APOPTOSIS; HYPERMETHYLATION; 5-METHYLCYTOSINE; CHEMORESISTANCE;

D O I：

10.1038/cddis.2014.149

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：e1183 / e1183

页数：13