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Theranostics 2023; 13(3):1198-1216. doi:10.7150/thno.79318 This issue Cite

Research Paper

PLK1-mediated phosphorylation of β-catenin enhances its stability and transcriptional activity for extracellular matrix remodeling in metastatic NSCLC

Da-Eun Kim¹, Sol-Bi Shin¹, Chang-Hyeon Kim¹, Yeo-Bin Kim¹, Hyun-Ji Oh¹, Hyungshin Yim^1,2✉

1. Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan, Gyeonggi-do 15588, Korea
2. Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do 15588, Korea

✉ Corresponding author: Hyungshin YIM, Address: Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do 15588, Korea. Phone: +82-31-400-5810 Fax: +82-31-400-5958 E-mail: hsyimac.kr More

Abstract

Rationale: β-catenin is a component for cell adhesion and a transcriptional coactivator in epithelial-mesenchymal transition (EMT). Previously we found that catalytically active PLK1 drives EMT in non-small cell lung cancer (NSCLC), upregulating extracellular matrix factors including TSG6, laminin γ2, and CD44. To understand the underlying mechanism and clinical significance of PLK1 and β-catenin in NSCLC, their relationship and function in metastatic regulation were investigated.

Methods: The clinical relevance between the survival rate of NSCLC patients and the expression of PLK1 and β-catenin was analyzed by a KM plot. Immunoprecipitation, kinase assay, LC-MS/MS spectrometry, and site-directed mutagenesis were performed to reveal their interaction and phosphorylation. A lentiviral doxycycline-inducible system, Transwell-based 3D culture, tail-vein injection model, confocal microscopy, and chromatin immunoprecipitation assays were used to elucidate the function of phosphorylated β-catenin in the EMT of NSCLC.

Results: Clinical analysis revealed that the high expression of CTNNB1/PLK1 was inversely correlated with the survival rates of 1,292 NSCLC patients, especially in metastatic NSCLC. In TGF-β-induced or active PLK1-driven EMT, β-catenin, PLK1, TSG6, laminin γ2, and CD44 were concurrently upregulated. β-catenin is a binding partner of PLK1 in TGF-β-induced EMT and is phosphorylated at S311. Phosphomimetic β-catenin promotes cell motility, invasiveness of NSCLC cells, and metastasis in a tail-vein injection mouse model. Its upregulated stability by phosphorylation enhances transcriptional activity through nuclear translocation for the expression of laminin γ2, CD44, and c-Jun, therefore enhancing PLK1 expression by AP-1.

Conclusions: Our findings provide evidence for the critical role of the PLK1/β-catenin/AP-1 axis in metastatic NSCLC, implying that β-catenin and PLK1 may serve as a molecular target and prognostic indicator of the therapeutic response in metastatic NSCLC patients.

Keywords: PLK1, β-catenin, AP-1, extracellular matrix, lung cancer

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