RESUMO
Metastasis of lung adenocarcinoma (LUAD) is a major cause of death in patients. Aryl hydrocarbon receptor (AHR), an important transcription factor, is involved in the initiation and progression of lung cancer. Polo-like kinase 1 (PLK1), a serine/threonine kinase, acts as an oncogene promoting the malignancy of multiple cancer types. However, the interaction between these two factors and their significance in lung cancer remain to be determined. In this study, we demonstrate that PLK1 phosphorylates AHR at S489 in LUAD, leading to epithelial-mesenchymal transition (EMT) and metastatic events. RNA-seq analyses reveal that type 2 deiodinase (DIO2) is responsible for EMT and enhanced metastatic potential. DIO2 converts tetraiodothyronine (T4) to triiodothyronine (T3), activating thyroid hormone (TH) signaling. In vitro and in vivo experiments demonstrate that treatment with T3 or T4 promotes the metastasis of LUAD, whereas depletion of DIO2 or a deiodinase inhibitor disrupts this property. Taking together, our results identify the AHR phosphorylation by PLK1 and subsequent activation of DIO2-TH signaling as mechanisms leading to LUAD metastasis. These findings can inform possible therapeutic interventions for this event.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Fosforilação , Iodeto Peroxidase/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Adenocarcinoma de Pulmão/genética , Hormônios Tireóideos/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Transição Epitelial-Mesenquimal/genética , Proliferação de Células/fisiologia , Quinase 1 Polo-LikeRESUMO
Metastasis of Lung adenocarcinoma (LUAD) is a major cause of death in patients. Aryl hydrocarbon receptor (AHR) is an important transcription factor involved in the initiation and progression of lung cancer. Polo-like kinase 1 (PLK1), a serine/threonine kinase, is an oncogene that promotes the malignancy of multiple cancer types. Nonetheless, the interaction between these two factors and significance in lung cancer remains to be determined. Here, we demonstrate that PLK1 phosphorylates AHR at S489 in LUAD, which leads to epithelial-mesenchymal transition (EMT) and metastatic events. RNA-seq analyses show that type 2 deiodinase (DIO2) is responsible for EMT and enhanced metastatic potential. DIO2 converts tetraiodothyronine (T4) to triiodothyronine (T3), which then activates thyroid hormone signaling. In vitro and in vivo experiments demonstrate that treatment with T3 or T4 promotes the metastasis of LUAD, whereas depletion of DIO2 or deiodinase inhibitor disrupts this property. Taken together, our results identify the phosphorylation of AHR by PLK1 as a mechanism leading to the progression of LUAD and provide possible therapeutic interventions for this event.