Chem Res Toxicol. 2021 Jul 19;34(7):1814-1821. doi: 10.1021/acs.chemrestox.1c00206. Epub 2021 Jul 2.
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 mA 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 mA, 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 mA 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.
他莫昔芬多年来一直用于治疗雌激素受体阳性乳腺癌；然而，耐药性是该疗法面临的主要挑战之一。我们发现，在他莫昔芬耐药（TamR）MCF-7 细胞中，ATF3 的蛋白表达水平明显高于相应的亲本癌细胞。此外，ATF3 蛋白表达与 TamR MCF-7 细胞对 4-羟基他莫昔芬（4-OHT）的耐药性呈正相关。从机制上讲，TamR MCF-7 细胞中 ATF3 蛋白表达水平升高是由于 YTHDF2（mA 读取蛋白）表达水平降低，导致 ATF3 mRNA 稳定性增加和翻译效率提高。此外，TamR MCF-7 细胞中 ATF3 mRNA 的 5'-非翻译区（5'-UTR）中 A131 的甲基化程度降低，A131 是 mA 的一个保守基序位点。此外，增强的 ATF3 刺激 ABCB1 的表达，ABC B1 是一种外排泵，赋予乳腺癌细胞耐药性，而 ATF3 本身也受到 4 型腺苷酸激酶的正调控。总之，我们的研究结果揭示了 mA 修饰的新分子靶标（即 ATF3 mRNA）和该靶标的表观转录调节因子（即 YTHDF2）。我们还阐明了 ATF3 在耐药性中的作用，揭示了其下游靶标（即 ABCB1），并提出 ATF3 是克服癌细胞耐药性的候选治疗靶点。
