eLife (Jul 2018)
An alternative splicing switch in FLNB promotes the mesenchymal cell state in human breast cancer
- Ji Li,
- Peter S Choi,
- Christine L Chaffer,
- Katherine Labella,
- Justin H Hwang,
- Andrew O Giacomelli,
- Jong Wook Kim,
- Nina Ilic,
- John G Doench,
- Seav Huong Ly,
- Chao Dai,
- Kimberly Hagel,
- Andrew L Hong,
- Ole Gjoerup,
- Shom Goel,
- Jennifer Y Ge,
- David E Root,
- Jean J Zhao,
- Angela N Brooks,
- Robert A Weinberg,
- William C Hahn
Affiliations
- Ji Li
- ORCiD
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States; Harvard Medical School, Boston, United States; Broad Institute of MIT and Harvard, Cambridge, United States
- Peter S Choi
- ORCiD
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States; Harvard Medical School, Boston, United States; Broad Institute of MIT and Harvard, Cambridge, United States
- Christine L Chaffer
- Whitehead Institute for Biomedical Research and MIT, Cambridge, United States; Garvan Institute of Medical Research, Sydney, Australia
- Katherine Labella
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States; Harvard Medical School, Boston, United States
- Justin H Hwang
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States; Harvard Medical School, Boston, United States; Broad Institute of MIT and Harvard, Cambridge, United States
- Andrew O Giacomelli
- ORCiD
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States; Harvard Medical School, Boston, United States; Broad Institute of MIT and Harvard, Cambridge, United States
- Jong Wook Kim
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States; Harvard Medical School, Boston, United States; Broad Institute of MIT and Harvard, Cambridge, United States
- Nina Ilic
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States; Harvard Medical School, Boston, United States; Broad Institute of MIT and Harvard, Cambridge, United States
- John G Doench
- Broad Institute of MIT and Harvard, Cambridge, United States
- Seav Huong Ly
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States; Harvard Medical School, Boston, United States; Broad Institute of MIT and Harvard, Cambridge, United States
- Chao Dai
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States; Harvard Medical School, Boston, United States; Broad Institute of MIT and Harvard, Cambridge, United States
- Kimberly Hagel
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States; Harvard Medical School, Boston, United States
- Andrew L Hong
- ORCiD
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States; Harvard Medical School, Boston, United States; Broad Institute of MIT and Harvard, Cambridge, United States
- Ole Gjoerup
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States; Harvard Medical School, Boston, United States; Broad Institute of MIT and Harvard, Cambridge, United States
- Shom Goel
- Harvard Medical School, Boston, United States; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
- Jennifer Y Ge
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States; Harvard Medical School, Boston, United States; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, United States
- David E Root
- Broad Institute of MIT and Harvard, Cambridge, United States
- Jean J Zhao
- Harvard Medical School, Boston, United States; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
- Angela N Brooks
- University of California, Santa Cruz, Santa Cruz, United States
- Robert A Weinberg
- Whitehead Institute for Biomedical Research and MIT, Cambridge, United States
- William C Hahn
- ORCiD
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States; Harvard Medical School, Boston, United States; Broad Institute of MIT and Harvard, Cambridge, United States
- DOI
- https://doi.org/10.7554/eLife.37184
- Journal volume & issue
-
Vol. 7
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
