Journal Article

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

Li, Chaohao, Imam, Ibrahim A., Liu, Jinghui, Allison, Derek B., Liu, Xiaoqi, Zhang, Yanquan, Wang, Ruixin, Wu, Sai, Shao, Qing, Rychahou, Piotr, Mao, Fengyi, Li, Zhiguo, Kong, Yifan, Wang, Xinyi, Wang, Chi, Zhang, Qiongsi, Rao, Xiongjian, He, Daheng, Evers, B. Mark

2023

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adenocarcinoma / Adenocarcinoma of Lung - genetics / Antibodies / Cancer / Cell cycle / Cell growth / Cell Proliferation - physiology / Cellular signal transduction / Development and progression / Epithelial-Mesenchymal Transition - genetics / Ethylenediaminetetraacetic acid / Gene expression / Genetic aspects / Health aspects / Humans / Iodide peroxidase / Iodide Peroxidase - metabolism / Iopanoic acid / Kinases / Laboratory animals / Lung cancer / Lung cancer, Non-small cell / Lung Neoplasms - genetics / Lung Neoplasms - pathology / Malignancy / Metastases / Metastasis / Mutagenesis / Mutation / Oncology, Experimental / Oxidoreductases / Phosphorylation / Plasmids / Polo-like kinase / Polo-Like Kinase 1 / Protein kinases / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Protein-serine/threonine kinase / Proteins / Receptors, Aryl Hydrocarbon - genetics / Tetracycline / Tetracyclines / Therapeutic applications / Thyroid cancer / Thyroid hormones / Thyroid Hormones - genetics / Thyroxine / Transcription factors / Triiodothyronine / Tumorigenesis