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

  1. Ji Li
  2. Peter S Choi
  3. Christine L Chaffer
  4. Katherine Labella
  5. Justin H Hwang
  6. Andrew O Giacomelli
  7. Jong Wook Kim
  8. Nina Ilic
  9. John G Doench
  10. Seav Huong Ly
  11. Chao Dai
  12. Kimberly Hagel
  13. Andrew L Hong
  14. Ole Gjoerup
  15. Shom Goel
  16. Jennifer Y Ge
  17. David E Root
  18. Jean J Zhao
  19. Angela N Brooks
  20. Robert A Weinberg
  21. William C Hahn  Is a corresponding author
  1. Dana-Farber Cancer Institute, United States
  2. Whitehead Institute for Biomedical Research, United States
  3. Broad Institute, United States
  4. Dana-Farber Cancer Institue, United States
  5. Harvard Medical School, United States
  6. University of California, Santa Cruz, United States
Research Article
  • Cited 10
  • Views 3,182
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Cite this article as: eLife 2018;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.

Article and author information

Author details

  1. Ji Li

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Peter S Choi

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Christine L Chaffer

    Whitehead Institute for Biomedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Katherine Labella

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Justin H Hwang

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Andrew O Giacomelli

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2109-0458
  7. Jong Wook Kim

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Nina Ilic

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. John G Doench

    Broad Institute, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Seav Huong Ly

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Chao Dai

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Kimberly Hagel

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Andrew L Hong

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0374-1667
  14. Ole Gjoerup

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Shom Goel

    Broad Institute, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Jennifer Y Ge

    Department of Medical Oncology, Dana-Farber Cancer Institue, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. David E Root

    Broad Institute, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Jean J Zhao

    Department of Cancer Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Angela N Brooks

    University of California, Santa Cruz, Santa Cruz, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Robert A Weinberg

    Whitehead Institute for Biomedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  21. William C Hahn

    Department of Medical Oncology, Dana-Farber Cancer Institue, Cambridge, United States
    For correspondence
    william_hahn@dfci.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2840-9791

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

  1. Douglas L Black, University of California, Los Angeles, United States

Publication history

  1. Received: April 1, 2018
  2. Accepted: July 24, 2018
  3. Accepted Manuscript published: July 30, 2018 (version 1)
  4. 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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