Fascin promotes lung cancer growth and metastasis by enhancing glycolysis and PFKFB3 expression

Shengchen Lin, Yunzhan Li, Dezhen Wang, Chongbiao Huang, David Marino, Oana Bollt, Chaodong Wu, Matthew D. Taylor, Wei Li, Gina M. DeNicola, Jihui Hao, Pankaj K. Singh, Shengyu Yang

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)230-242
Number of pages13
JournalCancer Letters
Volume518
DOIs
StatePublished - Oct 10 2021
Externally publishedYes

Keywords

  • Fascin inhibitor
  • Metabolism
  • YAP1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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