Biomedical Research Institute, INBIOMED, Department of Biochemistry, School of Medicine, University of Buenos Aires, CABA, Buenos Aires, Argentina.
Sci Rep. 2019 Jul 16;9(1):10324. doi: 10.1038/s41598-019-46776-7.
Acyl-CoA synthetase 4 (ACSL4) overexpression plays a causal role in the aggressiveness of triple negative breast cancer. In turn, a negative correlation has been established between ACSL4 and estrogen receptor alpha (ERα) expression. However, the upstream regulatory mechanisms leading to differential ACSL4 expression between triple negative breast cancer and ERα-positive cells remained unknown. We performed the characterization of the human ACSL4 promoter and the identification of transcription factors involved. Deletional analysis demonstrated the proximal 43 base pairs of the promoter are involved in overexpression. By site directed mutagenesis we describe that retinoid-related orphan receptor alpha (RORα), Sp1 and E2F elements are involved in the promoter activity. We established for the first time that estrogen-related receptor alpha (ERRα) is a transcription factor involved in the higher activation of the human ACSL4 promoter in breast cancer cells. Furthermore, a combination of inhibitors of ACSL4 and ERRα produced a synergistic decrease in MDA-MB-231 cell proliferation. We also demonstrated that ERα restoration in triple negative breast cancer cells downregulates ACSL4 expression. The results presented in this manuscript demonstrated transcriptional mechanism is involved in the different expression of ACSL4 in human breast cancer cell lines of different aggressiveness.
酰基辅酶 A 合成酶 4（ACSL4）过表达在三阴性乳腺癌的侵袭性中起因果作用。反过来，已经建立了 ACSL4 与雌激素受体α（ERα）表达之间的负相关关系。然而，导致三阴性乳腺癌和 ERα阳性细胞之间 ACSL4 表达差异的上游调节机制尚不清楚。我们对人 ACSL4 启动子进行了表征，并鉴定了涉及的转录因子。缺失分析表明，启动子的近端 43 个碱基参与了过表达。通过定点诱变，我们描述了视黄酸相关孤儿受体α（RORα）、Sp1 和 E2F 元件参与启动子活性。我们首次建立了雌激素相关受体α（ERRα）是参与乳腺癌细胞中人类 ACSL4 启动子更高激活的转录因子。此外，ACSL4 和 ERRα 的抑制剂联合使用可协同降低 MDA-MB-231 细胞的增殖。我们还证明了在三阴性乳腺癌细胞中恢复 ERα 会下调 ACSL4 的表达。本研究结果表明，转录机制参与了不同侵袭性的人乳腺癌细胞系中 ACSL4 的不同表达。
