1. Fascin promotes lung cancer growth and metastasis by enhancing glycolysis and PFKFB3 expression.
- Author
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Lin S, Li Y, Wang D, Huang C, Marino D, Bollt O, Wu C, Taylor MD, Li W, DeNicola GM, Hao J, Singh PK, and Yang S
- Subjects
- A549 Cells, Animals, Cell Line, Tumor, Female, Hep G2 Cells, Humans, Lung Neoplasms pathology, Mice, Mice, Nude, Neoplasm Metastasis pathology, Signal Transduction genetics, Transcription, Genetic genetics, YAP-Signaling Proteins genetics, Carrier Proteins genetics, Cell Proliferation genetics, Glycolysis genetics, Lung Neoplasms genetics, Microfilament Proteins genetics, Neoplasm Metastasis genetics, Phosphofructokinase-2 genetics
- Abstract
Fascin is a pro-metastatic actin-bundling protein that is upregulated in all metastatic carcinomas. Fascin promotes cancer cell migration and invasion by facilitating membrane protrusions, such as filopodia and invadopodia. Aerobic glycolysis is a key feature of cancer metabolism and provides critical intermediate metabolites for tumor growth. Here, we report that fascin increases glycolysis in lung cancer to promote tumor growth and metastasis. Fascin promotes glycolytic flux by increasing the expression and activities of phosphofructose-kinases 1 and 2 (PFK1 and 2). Fascin mediates glycolytic functions via activation of yes-associated protein 1 (YAP1) through its canonical actin-bundling activity by promoting the binding of YAP1 to a TEAD1/4 binding motif located 30 bp upstream of the PFKFB3 transcription start site to activate its transcription. Examination of the TCGA database suggests that the fascin-YAP1-PFKFB3 axis is likely conserved across different types of cancers. Importantly, pharmacological inhibitors of fascin suppressed YAP1-PFKFB3 signaling and glycolysis in cancer cell lines, organoid cultures, and xenograft metastasis models. Taken together, our data reveal that the glycolytic function of fascin is essential for the promotion of lung cancer growth and metabolism, and suggest that pharmacological inhibitors of fascin may be used to reprogram cancer metabolism in lung and potentially other cancers with fascin upregulation., (Copyright © 2021. Published by Elsevier B.V.)
- Published
- 2021
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