Early findings that PLK1 is highly expressed in cancer have driven an exploration of its functions in metastasis. However, whether PLK1 induces metastasis in vivo and its underlying mechanisms in NSCLC have not yet been determined. Here, we show that the expression of active PLK1 phosphorylated at T210, abundant in TGF-β-treated lung cells, potently induced metastasis in a tail-vein injection model. Active PLK1 with intact polo-box and ATP-binding domains accelerated cell motility and invasiveness by triggering EMT reprogramming, whereas a phosphomimetic version of p-S137-PLK1 did not, indicating that the phosphorylation status of PLK1 may determine the cell traits. Active PLK1-driven invasiveness upregulated TGF-β signaling and TSG6 encoded by TNFAIP6. Loss of TNFAIP6 disturbed the metastatic activity induced by active PLK1 or TGF-β. Clinical relevance shows that PLK1 and TNFAIP6 are strong predictors of poor survival rates in metastatic NSCLC patients. Therefore, we suggest that active PLK1 promotes metastasis by upregulating TGF-β signaling, which amplifies its metastatic properties by forming a positive feedback loop and that the PLK1/TGF-β-driven metastasis is effectively blocked by targeting PLK1 and TSG6, providing PLK1 and TSG6 as negative markers for prognostics and therapeutic targets in metastatic NSCLC.

The prerequisite function of vimentin for the epithelial–mesenchymal transition (EMT) is not clearly elucidated yet. Here, we show that vimentin phosphorylated by PLK1, triggers TGF-β-signaling, which consequently leads to metastasis and PD-L1 expression for immune suppression in lung adenocarcinoma. The clinical correlation between expression of both vimentin and PLK1, and overall survival rates of patients was significant in lung adenocarcinoma but not in squamous cell carcinoma. The phosphorylation of vimentin was accompanied by the activation of PLK1 during TGF-β-induced EMT in lung adenocarcinoma. Among the several phosphorylation sites determined by phospho-proteomic analysis and the site-specific mutagenesis, the phosphorylation at S339 displayed the most effective metastasis and tumourigenesis with the highest expression of PD-L1, compared with that of wild-type and other versions in both 3D cell culture and tail-vein injection metastasis models. Phosphomimetic vimentin at S339 interacted with p-Smad2 for its nuclear localization, leading to the expression of PD-L1. Clinical relevance revealed the inverse correlation between the survival rates of patients and the expressions of VIM, PLK1, and CD274 in primary and metastatic lung adenocarcinoma. Thus, PLK1-mediated phosphorylation of vimentin activates TGF-β signaling pathway, leading to the metastasis and immune escape through the expression of PD-L1, functioning as a shuttling protein in lung adenocarcinoma.

Epithelial-to-mesenchymal transition (EMT) is the first step in the development of the invasive and migratory properties of cancer metastasis. Since the transcriptional reprogramming of a number of genes occurs in EMT, the regulation of EMT transcription factors has been intensively investigated. EMT transcriptional factors are commonly classified by the direct or indirect repression of E-cadherin because one of hallmarks of EMT is the loss of E-cadherin. This facilitates the expression of genes for EMT, tumor invasion, and metastasis. The posttranslational modification of EMT transcriptional factors, such as Snail and Slug, directly regulates their functions, including their stability, nuclear localization, protein-protein interaction, and ubiquitination for the promotion or termination of EMT at the specific points. Here, we discuss how posttranslational modifications regulate gene expression in a dynamic and reversible manner by modifying upstream signaling pathways, focusing in particular on the posttranslational modifications of Snail, Slug, ZEB1, ZEB2, and TWIST1. This review demonstrates that EMT transcription factors regulate metastasis through their posttranslational modifications and that the flexibility and reversibility of EMT can be modified by phosphorylation.

Increased health awareness among the public has highlighted the health benefits of dietary supplements including flavonoids. As flavonoids target several critical factors to exert a variety of biological effects, studies to identify their target-specific effects have been conducted. Herein, we discuss the basic structures of flavonoids and their anticancer activities in relation to the specific biological targets acted upon by these flavonoids. Flavonoids target several signaling pathways involved in apoptosis, cell cycle arrest, mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/AKT kinase, and metastasis. Polo-like kinase 1 (PLK1) has been recognized as a valuable target in cancer treatment due to the prognostic implication of PLK1 in cancer patients and its clinical relevance between the overexpression of PLK1 and the reduced survival rates of several carcinoma patients. Recent studies suggest that several flavonoids, including genistein directly inhibit PLK1 inhibitory activity. Later, we focus on the anticancer effects of genistein through inhibition of PLK1.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.