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

// Nguyen Thi Thuy Phuong 1 , Sang Kyum Kim 2 , Ji Hye Im 1 , Jin Won Yang 1 , Min Chang Choi 1 , Sung Chul Lim 3 , Kwang Yeol Lee 4 , Young-Mi Kim 5 , Jeong Hoon Yoon 6 , Keon Wook Kang 1 1 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, South Korea 2 College of Pharmacy, Chungnam National University, Daejeon 305-764, South Korea 3 Department of Pathology, College of Medicine, Chosun University, Gwangju 501-759, South Korea 4 College of Pharmacy, Chonnam National University, Gwangju 500-757, South Korea 5 College of Pharmacy, Hanyang University, Ansan 426-791, South Korea 6 Department of Oral & Maxillofacial Pathology, College of Dentistry, Daejeon Dental Hospital, Wonkwang University, Daejeon 302-120, South Korea Correspondence to: Keon Wook Kang, e-mail: kwkang@snu.ac.kr Keywords: tamoxifen resistance, miR-146b, MAT2A, NF-κB, PTEN Received: January 07, 2015      Accepted: August 03, 2015      Published: September 18, 2015 ABSTRACT 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.