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

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.

Type Journal
ISBN 2050-084X (Electronic) 2050-084X (Linking)
Authors Li, J.; Choi, P. S.; Chaffer, C. L.; Labella, K.; Hwang, J. H.; Giacomelli, A. O.; Kim, J. W.; Ilic, N.; Doench, J. G.; Ly, S. H.; Dai, C.; Hagel, K.; Hong, A. L.; Gjoerup, O.; Goel, S.; Ge, J. Y.; Root, D. E.; Zhao, J. J.; Brooks, A. N.; Weinberg, R. A.; Hahn, W. C.
Responsible Garvan Author A/Prof Christine Chaffer
Publisher Name eLife
Published Date 2018-07-30
Published Volume 7
Published Pages e37184
Status Always Electronic
DOI 10.7554/eLife.37184
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/30059005
OpenAccess link to author's accepted manuscript version https://publications.gimr.garvan.org.au/open-access/14658