An alternative splicing switch in FLNB promotes the mesenchymal cell state in human breast cancer

Elife. 2018 Jul 30;7:e37184. doi: 10.7554/eLife.37184.

Abstract

Alternative splicing of mRNA precursors represents a key gene expression regulatory step and permits the generation of distinct protein products with diverse functions. In a genome-scale expression screen for inducers of the epithelial-to-mesenchymal transition (EMT), we found a striking enrichment of RNA-binding proteins. We validated that QKI and RBFOX1 were necessary and sufficient to induce an intermediate mesenchymal cell state and increased tumorigenicity. Using RNA-seq and eCLIP analysis, we found that QKI and RBFOX1 coordinately regulated the splicing and function of the actin-binding protein FLNB, which plays a causal role in the regulation of EMT. Specifically, the skipping of FLNB exon 30 induced EMT by releasing the FOXC1 transcription factor. Moreover, skipping of FLNB exon 30 is strongly associated with EMT gene signatures in basal-like breast cancer patient samples. These observations identify a specific dysregulation of splicing, which regulates tumor cell plasticity and is frequently observed in human cancer.

Keywords: EMT; FLNB; QKI; RBFOX1; alternative splicing; basal-like breast cancer; cancer biology; cell biology; human; mouse.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics*
  • Animals
  • Base Sequence
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition / genetics
  • Exons / genetics
  • Female
  • Filamins / genetics*
  • Filamins / metabolism
  • Gene Expression Regulation, Neoplastic
  • Genome, Human
  • Humans
  • Hyaluronan Receptors / metabolism
  • Mesenchymal Stem Cells / metabolism*
  • Mice, Nude
  • Neoplasm Proteins / metabolism
  • Open Reading Frames / genetics
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / metabolism
  • Reproducibility of Results

Substances

  • FLNB protein, human
  • Filamins
  • Hyaluronan Receptors
  • Neoplasm Proteins
  • Protein Isoforms
  • RNA, Messenger
  • RNA-Binding Proteins