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

Authors
Nguyen Thi Thuy PhuongKim, Sang KyumIm, Ji HyeYang, Jin WonChoi, Min ChangLim, Sung ChulLee, Kwang YeolKim, Young-MiYoon, Jeong HoonKang, Keon Wook
Issue Date
Mar-2016
Publisher
IMPACT JOURNALS LLC
Keywords
tamoxifen resistance; miR-146b; MAT2A; NF-kappa B; PTEN
Citation
ONCOTARGET, v.7, no.12, pp.13902 - 13916
Indexed
SCIE
SCOPUS
Journal Title
ONCOTARGET
Volume
7
Number
12
Start Page
13902
End Page
13916
URI
https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/14146
DOI
10.18632/oncotarget.5298
ISSN
1949-2553
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-kappa B, 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-kappa B 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-kappa B-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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