An alternative splicing switch in FLNB promotes the mesenchymal cell state in human breast cancer
- Dana-Farber Cancer Institute, United States
- Whitehead Institute for Biomedical Research, United States
- Broad Institute, United States
- Dana-Farber Cancer Institue, United States
- Harvard Medical School, United States
- University of California, Santa Cruz, United States
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.
Data availability
Both the RNA-seq data and the CLIP-seq data are deposited at NCBI Gene Expression Omnibus (accession number GSE98210).
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Alternative splicing regulated by QKI and RBFOX1 promotes the mesenchymal cell state in breast cancerPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE98210).
Article and author information
Author details
Andrew O Giacomelli
Funding
National Cancer Institute (R01 CA130988)
- William C Hahn
National Cancer Institute (U01 CA176058)
- William C Hahn
Susan G. Komen (PDF14300517)
- Ji Li
Terri Brodeur Breast Cancer Foundation grant
- Ji Li
National Cancer Institute (K99 CA208028)
- Peter S Choi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study with use of animals was performed in accordance to the protocol (04-101) approved by Dana-Farber Cancer Institute (DFCI)'s Institutional Animal Care and Use Committee (IACUC). The animals were handled according to the Guide for the Care and Use of Laboratory Animals of the National Institute of Health.
Reviewing Editor
- Douglas L Black, University of California, Los Angeles, United States
Publication history
- Received: April 1, 2018
- Accepted: July 24, 2018
- Accepted Manuscript published: July 30, 2018 (version 1)
- Version of Record published: August 21, 2018 (version 2)
Copyright
© 2018, Li et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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An alternative splicing switch in FLNB promotes the mesenchymal cell state in human breast cancer
eLife 7:e37184.
https://doi.org/10.7554/eLife.37184
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