Department of Pathology, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, the First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China.
Department of Dermatology, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, the First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China.
Bioengineered. 2021 Dec;12(1):1874-1889. doi: 10.1080/21655979.2021.1924544.
Excessive activation of signal transducer and activator of transcription 3 (STAT3) is implicated in breast cancer (BC) chemoresistance, but its underlying mechanism is not fully understood. There are STAT3 binding sites in fat mass and obesity-associated protein (FTO) promoter region, thus STAT3 may regulate the transcription of FTO. This study aimed to investigate the correlation between FTO and STAT3 in BC chemoresistance. Herein, FTO and STAT3 were highly expressed in doxorubicin-resistant BC (BC-DoxR) cells. CHIP assay verified the binding between STAT3 and FTO promoter in BC-DoxR cells. Dual luciferase reporter assay showed that FTO promoter activity was inhibited by S3I-201 (STAT3 inhibitor) but enhanced by epidermal growth factor (EGF, STAT3 activator) in BC-DoxR and BC cells. FTO mRNA and protein expression were suppressed by S3I-201 in BC-DoxR cells and EGF-stimulated BC cells. Notably, FTO regulated total N6-methyladenosine (m6A) levels in BC-DoxR and BC cells but could not affect STAT3 mRNA expression, indicating that FTO was not involved in the m6A modification of STAT3. However, FTO could activate STAT3 signaling in BC-DoxR and BC cells. Besides, FTO knockdown inhibited the doxorubicin resistance of BC-DoxR cells, while FTO overexpression enhanced the doxorubicin resistance and weakened the doxorubicin sensitivity of BC cells. Moreover, decreased doxorubicin resistance by STAT3 knockdown was abolished by FTO overexpression and decreased doxorubicin sensitivity by STAT3 overexpression was reversed by FTO knockdown, indicating that FTO was implicated in STAT3-mediated doxorubicin resistance and impairment of doxorubicin sensitivity of BC cells. Altogether, our findings provide a mechanism underlying BC doxorubicin resistance.
信号转导子和转录激活子 3（STAT3）的过度激活与乳腺癌（BC）的化疗耐药有关，但其中的机制尚不完全清楚。脂肪量和肥胖相关蛋白（FTO）启动子区域存在 STAT3 结合位点，因此 STAT3 可能调节 FTO 的转录。本研究旨在探讨 FTO 与 BC 化疗耐药中的 STAT3 之间的相关性。在此，阿霉素耐药 BC（BC-DoxR）细胞中 FTO 和 STAT3 的表达水平较高。CHIP 实验验证了 BC-DoxR 细胞中 STAT3 与 FTO 启动子的结合。双荧光素酶报告基因实验表明，在 BC-DoxR 和 BC 细胞中，FTO 启动子活性被 S3I-201（STAT3 抑制剂）抑制，但被表皮生长因子（EGF，STAT3 激活剂）增强。S3I-201 可抑制 BC-DoxR 细胞和 EGF 刺激的 BC 细胞中的 FTO mRNA 和蛋白表达。值得注意的是，FTO 调节 BC-DoxR 和 BC 细胞中的总 N6-甲基腺苷（m6A）水平，但不能影响 STAT3 mRNA 表达，表明 FTO 不参与 STAT3 的 m6A 修饰。然而，FTO 可激活 BC-DoxR 和 BC 细胞中的 STAT3 信号通路。此外，FTO 敲低抑制了 BC-DoxR 细胞的阿霉素耐药性，而过表达 FTO 则增强了 BC 细胞的阿霉素耐药性并减弱了其对阿霉素的敏感性。此外，STAT3 敲低导致的阿霉素耐药性降低被 FTO 过表达所消除，而 STAT3 过表达导致的阿霉素敏感性降低被 FTO 敲低所逆转，表明 FTO 参与了 STAT3 介导的 BC 细胞阿霉素耐药性和阿霉素敏感性的损害。总之，我们的研究结果为 BC 阿霉素耐药性提供了一种机制。
