Foxk2 inhibits non-small cell lung cancer epithelial-mesenchymal transition and proliferation through the repression of different key target genes

Abstract

Increasing evidence suggests that numerous fork-head transcription factors are required to repress the mammalian cells phenotype. Among them, Foxk2 is a ubiquitously expressed family member, but the role of Foxk2 in mediating tumor metastasis in non-small cell lung cancer has not been explored. In this investigation reduced Foxk2 expression was found in lung adenocarcinoma tissues compared with the adjacent non-tumor tissues, and was associated with better overall survival. Low expression was also found in the NSCLC cell lines such as A549, NCI-H520, H1299, H358 and H460 cells. Recombinant lentivirus expressing Foxk2 constructs or ShFoxk2 were developed and transfected into A549 cells or NCI-H520 cells, immunofluorescence assay, qRT-PCR, and western blot analysis were used to measure the change of the epithelial markers, E-cadherin and α-catenin, and mesenchymal markers N-cadherin and vimentin. Wound healing assay and Transwell assay were used to measure the relative cell invasion ability. MTT assay, Edu assay, and cell cycle distribution analysis were used to confirm the effect of Foxk2 on cell proliferation. ChIP-seq, qChIP, as well as luciferase reporter gene assays were used to detect the target genes regulated by Foxk2, Bioinformatics predicated the potential miRNAs that could target Foxk2. Our study demonstrated that Foxk2 played major roles in NSCLC EMT by directly targeting N-cadherin and Snail, we found that Foxk2 regulated NSCLC cell growth by suppressing the expression of cyclin D1 and CDK4, which suggested that Foxk2 might be a multifunctional regulator in NSCLC. The expression of Foxk2 may be regulated by miR-1271, which could serve as a promising therapeutic target for NSCLC.

Forkhead box K2 inhibits the proliferation, migration, and invasion of human glioma cells and predicts a favorable prognosis

“… 4 , 5 Recently, researchers found that FOXK2 plays a crucial role in the occurrence and development of various tumors, and a high expression of FOXK2 is correlated with poor survival. 6 – 8 Chen et al 8 found that overexpression of FOXK2 suppresses epithelial-to-mesenchymal transition (EMT) in non-small cell lung cancer, inhibiting the expression of N-cadherin and Snail. However, Lin et al 9 found that FOXK2 expression increased in hepatocellular carcinoma.…”

Downregulation of FOXK2 is associated with poor prognosis in patients with gastric cancer

“…Forkhead box (FOX)K2 is a member of the FOX transcription factor family; FOXK2 is a vital protein that is phosphorylated by the cyclin-dependent kinase (CDK) complex ( 7 ). FOXK2 regulates numerous genes involved in cell adhesion, motility, metabolism, apoptosis and tumorigenesis ( 8 , 9 ). Previous research has demonstrated that the overexpression of FOXK2 suppresses EMT in non-small cell lung cancer, through inhibition of N-cadherin and β-catenin expression ( 10 ).…”

Development of a novel transcription factors-related prognostic signature for serous ovarian cancer

“…The function of FOXK2 is context and tumor-speci c, and it might serve as an oncogene and tumor suppressor in different cancers [47]. It was reported that FOXK2 inhibited cell proliferation and invasion in breast cancer, non-small cell lung cancer (NSCLC), clear-cell renal cell carcinoma, gastric cancer, and indicated favorable prognosis [48][49][50][51]. However, it promoted cell growth and indicated unfavorable prognosis in colorectal cancer and hepatocellular carcinoma [52,53].…”