title: Induction of methionine adenosyltransferase 2A in tamoxifen-resistant breast cancer cells.
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.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Nguyen Thi Thuy
authors.initials: NT
authors.lastname: Phuong
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, South Korea.
authors.forename: Sang Kyum
authors.initials: SK
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Im
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Jin Won
authors.initials: JW
authors.lastname: Yang
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Min Chang
authors.initials: MC
authors.lastname: Choi
authors.affiliation: Department of Pathology, College of Medicine, Chosun University, Gwangju 501-759, South Korea.
authors.forename: Sung Chul
authors.initials: SC
authors.lastname: Lim
authors.affiliation: College of Pharmacy, Chonnam National University, Gwangju 500-757, South Korea.
authors.forename: Kwang Yeol
authors.initials: KY
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Hanyang University, Ansan 426-791, South Korea.
authors.forename: Young-Mi
authors.initials: YM
authors.lastname: Kim
authors.affiliation: Department of Oral & Maxillofacial Pathology, College of Dentistry, Daejeon Dental Hospital, Wonkwang University, Daejeon 302-120, South Korea.
authors.forename: Jeong Hoon
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Keon Wook
authors.initials: KW
authors.lastname: Kang
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008716:Methionine Adenosyltransferase / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012436:S-Adenosylmethionine / Q000378:metabolism; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D013629:Tamoxifen; D012436:S-Adenosylmethionine; C527161:MAT2A protein, human; D008716:Methionine Adenosyltransferase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: MAT2A; NF-κB; PTEN; miR-146b; tamoxifen resistance