Phosphorylation of AHR by PLK1 promotes metastasis of LUAD via DIO2-TH signaling

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.Author summary: The spread of lung cancer cells to other parts of the body is a major reason why people with this cancer often do not survive. We studied two important proteins in lung cancer: aryl hydrocarbon receptor (AHR) and Polo-like kinase 1 (PLK1), which are known to worsen many types of cancer. Our research found that PLK1 interacted with AHR in a process called phosphorylation. This interaction initiated a process called epithelial-mesenchymal transition (EMT) in cancer cells, helping them spread to other parts of the body. We also discovered that another molecule called type 2 deiodinase (DIO2) was responsible for this process. DIO2 converted one type of thyroid hormone (T4) into another (T3), which then sent signals that aided the spread of cancer cells. When we exposed lung cancer cells to more T3 or T4, they spread more. However, when we inhibited DIO2, the cancer cells could not spread as much. Our research demonstrated that the interaction between AHR and PLK1, the role of DIO2, and thyroid hormones were significant factors in lung cancer cells spread. Understanding this could help us discover new ways to stop or slow down this undesired process.