Research Papers:

Induction of methionine adenosyltransferase 2A in tamoxifen-resistant breast cancer cells

Nguyen Thi Thuy Phuong, Sang Kyum Kim, Ji Hye Im, Jin Won Yang, Min Chang Choi, Sung Chul Lim, Kwang Yeol Lee, Young Mi Kim, Jeong Hoon Yoon and Keon Wook Kang _

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Oncotarget. 2016; 7:13902-13916. https://doi.org/10.18632/oncotarget.5298

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Nguyen Thi Thuy Phuong1, Sang Kyum Kim2, Ji Hye Im1, Jin Won Yang1, Min Chang Choi1, Sung Chul Lim3, Kwang Yeol Lee4, Young-Mi Kim5, Jeong Hoon Yoon6, Keon Wook Kang1

1College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, South Korea

2College of Pharmacy, Chungnam National University, Daejeon 305-764, South Korea

3Department of Pathology, College of Medicine, Chosun University, Gwangju 501-759, South Korea

4College of Pharmacy, Chonnam National University, Gwangju 500-757, South Korea

5College of Pharmacy, Hanyang University, Ansan 426-791, South Korea

6Department of Oral & Maxillofacial Pathology, College of Dentistry, Daejeon Dental Hospital, Wonkwang University, Daejeon 302-120, South Korea

Correspondence to:

Keon Wook Kang, e-mail: [email protected]

Keywords: tamoxifen resistance, miR-146b, MAT2A, NF-κB, PTEN

Received: January 07, 2015     Accepted: August 03, 2015     Published: September 18, 2015


We previously showed that S-adenosylmethionine-mediated hypermethylation of the PTEN promoter was important for the growth of tamoxifen-resistant MCF-7 (TAMR-MCF-7) cancer cells. Here, we found that the basal expression level of methionine adenosyltransferase 2A (MAT2A), a critical enzyme for the biosynthesis of S-adenosylmethionine, was up-regulated in TAMR-MCF-7 cells compared with control MCF-7 cells. Moreover, the basal expression level of MAT2A in T47D cells, a TAM-resistant estrogen receptor-positive cell line was higher compared to MCF-7 cells. Immunohistochemistry confirmed that MAT2A expression in TAM-resistant human breast cancer tissues was higher than that in TAM-responsive cases. The promoter region of human MAT2A contains binding sites for nuclear factor-κB, activator protein-1 (AP-1), and NF-E2-related factor 2 (Nrf2), and the activities of these three transcription factors were enhanced in TAMR-MCF-7 cells. Both the protein expression and transcriptional activity of MAT2A in TAMR-MCF-7 cells were potently suppressed by NF-κB inhibition but not by c-Jun/AP-1 or Nrf2 knock-down. Interestingly, the expression levels of microRNA (miR)-146a and -146b were diminished in TAMR-MCF-7 cells, and miR-146b transduction decreased NF-κB-mediated MAT2A expression. miR-146b restored PTEN expression via the suppression of PTEN promoter methylation in TAMR-MCF-7 cells. Additionally, miR-146b overexpression inhibited cell proliferation and reversed chemoresistance to 4-hydroxytamoxifen in TAMR-MCF-7 cells.

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