Abstract
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.
Document Type
Article
Publication Date
11-2023
Digital Object Identifier (DOI)
https://doi.org/10.1371/journal.pgen.1011017
Funding Information
This study is supported by NIH R01 CA157429 (XL), R01 CA196634 (XL), R01 CA264652 (XL), R01 CA256893 (XL), R01 CA266579 (ZL), as well as the Biospecimen Procurement & Translational Pathology, Biostatistics and Bioinformatics, Redox Metabolism, and Flow Cytometry and Immune Monitoring Shared Resources of the University of Kentucky Markey Cancer Center (P30 CA177558). The following authors receive financial support from the funder listed below: Chaohao Li (R01 CA264652); Derek B. Allison (P30 CA177558); Fengyi mao (R01 CA264652); Xinyi Wang (R01 CA256893); Yifan Kong (R01 CA157429); Qiongsi Zhang (R01 CA196634); Yanquan Zhang (R01 CA196634); Jinghui Liu (R01 CA256893); Ruixin Wang (R01 CA157429); Xiongjian Rao (R01 CA196634); Sai Wu (R01 CA264652); Chi Wang (R01 CA256893, R01 CA264652, P30 CA177558); Zhiguo Li (R01 CA266579); Xiaoqi Liu (R01 CA264652, R01 CA196634, R01 CA256893, R01 CA157429). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Repository Citation
Li, Chaohao; Allison, Derek B.; He, Daheng; Mao, Fengyi; Wang, Xinyi; Rychahou, Piotr G.; Imam, Ibrahim A.; Kong, Yifan; Zhang, Qiongsi; Zhang, Yanquan; Liu, Jinghui; Wang, Ruixin; Rao, Xiongjian; Wu, Sai; Evers, B. Mark; Shao, Qing; Wang, Chi; Li, Zhiguo; and Liu, Xiaoqi, "Phosphorylation of AHR by PLK1 promotes metastasis of LUAD via DIO2-TH signaling" (2023). Markey Cancer Center Faculty Publications. 379.
https://uknowledge.uky.edu/markey_facpub/379
Included in
Ecology and Evolutionary Biology Commons, Genetics Commons, Molecular Biology Commons, Oncology Commons
Notes/Citation Information
© 2023 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.