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

作者：Li Ji; Choi Peter S; Chaffer Christine L; Labella Katherine; Hwang Justin H; Giacomelli Andrew O; Kim Jong Wook; Ilic Nina; Doench John G; Ly Seav Huong; Dai Chao; Hagel Kimberly; Hong Andrew L; Gjoerup Ole; Goel Shom; Ge Jennifer Y; Root David E; Zhao Jean J; Brooks Angela N; Weinberg Robert A; Hahn William C^*

来源：eLife, 2018, 7: e37184.

DOI：10.7554/eLife.37184

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.

• 出版日期2018-7-30