转录因子 TBX5 的过表达抑制 YAP1-TEAD1 通路的激活，从而促进肺癌细胞中的铁死亡。
Overexpression of transcription factor TBX5 inhibits the activation of YAP1-TEAD1 pathway to promote ferroptosis in lung cancer cells.
机构信息
General Medicine Department, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, PR China.
Medical College, Hunan University of Medicine, Huaihua, 418000, Hunan, PR China.
出版信息
Biochem Biophys Res Commun. 2024 Jul 23;718:150037. doi: 10.1016/j.bbrc.2024.150037. Epub 2024 Apr 30.
BACKGROUND
Non-small cell lung cancer (NSCLC) accounts for more than 80 % of lung cancer (LC) cases, making it the primary cause of cancer-related mortality worldwide. T-box transcription factor 5 (TBX5) is an important regulator of embryonic and organ development and plays a key role in cancer development. Here, our objective was to investigate the involvement of TBX5 in ferroptosis within LC cells and the underlying mechanisms.
METHODS
First, TBX5 expression was examined in human LC cells. Next, overexpression of TBX5 and Yes1-associated transcriptional regulator (YAP1) and knockdown of TEA domain 1 (TEAD1) were performed in A549 and NCI-H1703 cells. The proliferation ability of A549 and NCI-H1703 cells, GSH, MDA, ROS, and Fe levels were measured. Co-immunoprecipitation (Co-IP) was performed to verify whether TBX5 protein could bind YAP1. Then TBX5, YAP1, TEAD1, GPX4, p53, FTH1, SLC7A11 and PTGS2 protein levels were assessed. Finally, we verified the effect of TBX5 on ferroptosis in LC cells in vivo.
RESULTS
TBX5 expression was down-regulated in LC cells, especially in A549 and NCI-H1703 cells. Overexpression of TBX5 significantly decreased proliferation ability of A549 and NCI-H1703 cells, downregulated GPX4 and GSH levels, and upregulated MDA, ROS, and Fe levels. Co-IP verified that TBX5 protein could bind YAP1. Moreover, oe-YAP1 promoted proliferation ability of A549 and NCI-H1703 cells transfected with Lv-TBX5, upregulated GPX4 and GSH levels and downregulated MDA, ROS, and Fe levels. Additionally, oe-YAP1 promoted FTH1 and SLC7A11 levels and inhibited p53 and PTGS2 levels in A549 and NCI-H1703 cells transfected with Lv-TBX5. However, transfection with si-TEAD1 further reversed these effects. In vivo experiments further validated that TBX5 promoted ferroptosis in LC cells.
CONCLUSIONS
TBX5 inhibited the activation of YAP1-TEAD1 pathway to promote ferroptosis in LC cells.
背景
非小细胞肺癌（NSCLC）占肺癌（LC）病例的 80%以上，是全球癌症相关死亡的主要原因。T 框转录因子 5（TBX5）是胚胎和器官发育的重要调节剂，在癌症发展中起关键作用。在这里，我们的目的是研究 TBX5 参与 LC 细胞中的铁死亡以及潜在的机制。
方法
首先，检测人 LC 细胞中的 TBX5 表达。然后，在 A549 和 NCI-H1703 细胞中过表达 TBX5 和 Yes1 相关转录调节剂（YAP1）并敲低 TEA 结构域 1（TEAD1）。测量 A549 和 NCI-H1703 细胞的增殖能力、GSH、MDA、ROS 和 Fe 水平。进行免疫共沉淀（Co-IP）以验证 TBX5 蛋白是否能与 YAP1 结合。然后评估 TBX5、YAP1、TEAD1、GPX4、p53、FTH1、SLC7A11 和 PTGS2 蛋白水平。最后，我们验证了 TBX5 在体内对 LC 细胞铁死亡的影响。
结果
TBX5 在 LC 细胞中表达下调，特别是在 A549 和 NCI-H1703 细胞中。TBX5 的过表达显著降低了 A549 和 NCI-H1703 细胞的增殖能力，下调了 GPX4 和 GSH 水平，上调了 MDA、ROS 和 Fe 水平。Co-IP 验证了 TBX5 蛋白可以与 YAP1 结合。此外，oe-YAP1 促进了转染 Lv-TBX5 的 A549 和 NCI-H1703 细胞的增殖能力，上调了 GPX4 和 GSH 水平，下调了 MDA、ROS 和 Fe 水平。此外，oe-YAP1 促进了 A549 和 NCI-H1703 细胞中转染 Lv-TBX5 的 FTH1 和 SLC7A11 水平，并抑制了 p53 和 PTGS2 水平。然而，转染 si-TEAD1 进一步逆转了这些作用。体内实验进一步验证了 TBX5 促进了 LC 细胞中的铁死亡。
结论
TBX5 抑制 YAP1-TEAD1 通路的激活，从而促进 LC 细胞中的铁死亡。
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