Open AccessATF3 Modulates the Resistance of Breast Cancer Cells to Tamoxifen through an N6-Methyladenosine-Based Epitranscriptomic Mechanism
Author(s) -
Xiaochuan Liu,
Jun Yuan,
Xudong Zhang,
Lin Li,
Xiaoxia Dai,
Qi Chen,
Yinsheng Wang
Publication year - 2021
Publication title -
chemical research in toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.031
H-Index - 156
eISSN - 1520-5010
pISSN - 0893-228X
DOI - 10.1021/acs.chemrestox.1c00206
Subject(s) - mechanism (biology) , breast cancer , tamoxifen , cancer , cancer research , chemistry , biology , bioinformatics , oncology , medicine , physics , quantum mechanics
Tamoxifen has been used for years for treating estrogen receptor-positive breast cancer; drug resistance, however, constitutes one of the main challenges for this therapy. We found that the protein expression level of ATF3 is significantly higher in tamoxifen-resistant (TamR) MCF-7 cells than the corresponding parental cancer cells. In addition, ATF3 protein expression is positively correlated with the resistance of TamR MCF-7 cells to 4-hydroxytamoxifen (4-OHT). Mechanistically, elevated ATF3 protein expression in TamR MCF-7 cells results from a lower level of expression of YTHDF2, an m 6 A reader protein, and the ensuing stabilization and increased translational efficiency of ATF3 mRNA. Additionally, TamR MCF-7 cells exhibited decreased methylation at A131, a consensus motif site for m 6 A, in the 5'-untranslated region (5'-UTR) of ATF3 mRNA. Moreover, augmented ATF3 stimulates the expression of ABCB1, an efflux pump that confers drug resistance in breast cancer cells, and ATF3 itself is also positively regulated by adenylate kinase 4. Together, our results uncovered a novel molecular target for m 6 A modification (i.e., ATF3 mRNA) and the epitranscriptomic regulator for this target (i.e., YTHDF2). We also illustrated the role of ATF3 in drug resistance, revealed its downstream target (i.e., ABCB1), and suggested ATF3 as a candidate therapeutic target for overcoming drug resistance in cancer cells.