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

• Published in: Oncotarget Vol. 7; no. 12; pp. 13902 - 13916
• Main Authors: Phuong, Nguyen Thi Thuy, Kim, Sang Kyum, Im, Ji Hye, Yang, Jin Won, Choi, Min Chang, Lim, Sung Chul, Lee, Kwang Yeol, Kim, Young-Mi, Yoon, Jeong Hoon, Kang, Keon Wook
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 22-03-2016
• Subjects: Antineoplastic Agents, Hormonal - pharmacology; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Proliferation; DNA Methylation; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; Methionine Adenosyltransferase - genetics; Methionine Adenosyltransferase - metabolism; MicroRNAs - genetics; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; NF-kappa B - genetics; NF-kappa B - metabolism; Promoter Regions, Genetic; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; Research Paper; S-Adenosylmethionine - metabolism; Signal Transduction; Tamoxifen - pharmacology; Transcription Factor AP-1 - genetics; Transcription Factor AP-1 - metabolism; Tumor Cells, Cultured; PTEN; NF-κB; miR-146b; tamoxifen resistance; MAT2A
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.5298

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.