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Novel mechanistic targets of forkhead box Q1 transcription factor in human breast cancer cells.

ABSTRACT: The transcription factor forkhead box Q1 (FoxQ1) is overexpressed in different solid tumors including breast cancer, but the mechanism underlying its oncogenic function is still not fully understood. In this study, we compared RNA-seq data from FoxQ1 overexpressing SUM159 cells with that of empty vector-transfected control cells to identify novel mechanistic targets of this transcription factor. Analysis of The Cancer Genome Atlas (TCGA) data set revealed significantly higher expression of FoxQ1 in black breast cancer patients compared with white women with this disease. In contrast, expression of FoxQ1 was comparable in ductal and lobular carcinomas in the breast cancer TCGA data set. Complementing our published findings in basal-like subtype, immunohistochemistry revealed upregulation of FoxQ1 protein in luminal-type human breast cancer tissue microarrays when compared with normal mammary tissues. Many previously reported transcriptional targets of FoxQ1 (eg, E-cadherin, N-cadherin, fibronectin 1, etc) were verified from the RNA-seq analysis. FoxQ1 overexpression resulted in the downregulation of genes associated with cell cycle checkpoints, M phase, and cellular response to stress/external stimuli as evidenced from the Reactome pathway analysis. Consequently, FoxQ1 overexpression resulted in mitotic arrest in basal-like SUM159 and human mammary epithelial cell line, but not in luminal-type MCF-7 cells. Finally, we show for the first time that FoxQ1 is a direct transcriptional regulator of interleukin (IL)-1α, IL-8, and vascular endothelial growth factor in breast cancer cells as evidenced by chromatin immunoprecipitation assay. In conclusion, the present study reports novel mechanistic targets of FoxQ1 in human breast cancer cells.

SUBMITTER: Kim SH

PROVIDER: S-EPMC7484420 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundColorectal cancer (CRC) is an extremely malignant tumor with a high mortality rate. Little is known about the mechanism by which forkhead Box q1 (FOXQ1) causes CRC invasion and metastasis through the epidermal growth factor receptor (EGFR) pathway.AimTo illuminate the mechanism by which FOXQ1 promotes the invasion and metastasis of CRC by activating the heparin binding epidermal growth factor (HB-EGF)/EGFR pathway.MethodsWe investigated the differential expression and prognosis of FOXQ1 and HB-EGF in CRC using the Gene Expression Profiling Interactive Analysis (GEPIA) website (http://gepia.cancer-pku.cn/index.html). Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to detect the expression of FOXQ1 and HB-EGF in cell lines and tissues, and we constructed a stable low-expressing FOXQ1 cell line and verified it with the above method. The expression changes of membrane-bound HB-EGF (proHB-EGF) and soluble HB-EGF (sHB-EGF) in the low-expressing FOXQ1 cell line were detected by flow cytometry and ELISA. Western blotting was used to detect changes in the expression levels of HB-EGF and EGFR pathway-related downstream genes when exogenous recombinant human HB-EGF was added to FOXQ1 knockdown cells. Proliferation experiments, transwell migration experiments, and scratch experiments were carried out to determine the mechanism by which FOXQ1 activates the EGFR signaling pathway through HB-EGF, and then to evaluate the clinical relevance of FOXQ1 and HB-EGF.ResultsGEPIA showed that the expression of FOXQ1 in CRC tissues was relatively high and was related to a lower overall survival rate. PCR array results showed that FOXQ1 is related to the HB-EGF and EGFR pathways. Knockdown of FOXQ1 suppressed the expression of HB-EGF, and led to a decrease in EGFR and its downstream genes AKT, RAF, KRAS expression levels. After knockdown of FOXQ1 in CRC cell lines, cell proliferation, migration and invasion were attenuated. Adding HB-EGF restored the migration and invasion ability of CRC, but not the cell proliferation ability. Kaplan-Meier survival analysis results showed that the combination of FOXQ1 and HB-EGF may serve to predict CRC survival.ConclusionBased on these collective data, we propose that FOXQ1 promotes the invasion and metastasis of CRC via the HB-EGF/EGFR pathway.

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Novel mechanistic targets of forkhead box Q1 transcription factor in human breast cancer cells.

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