1. Cancer Biology
  2. Cell Biology

KSR1-and ERK-dependent translational regulation of the epithelial-to-mesenchymal transition

  1. Chaitra Rao
  2. Danielle E Frodyma
  3. Siddesh Southekal
  4. Robert A Svoboda
  5. Adrian R Black
  6. Chittibabu Guda
  7. Tomohiro Mizutani
  8. Hans Clevers
  9. Keith R Johnson
  10. Kurt W Fisher
  11. Robert E Lewis  Is a corresponding author
  1. University of Nebraska Medical Center, United States
  2. Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Netherlands
https://doi.org/10.7554/eLife.66608
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  1. Chaitra Rao
  2. Danielle E Frodyma
  3. Siddesh Southekal
  4. Robert A Svoboda
  5. Adrian R Black
  6. Chittibabu Guda
  7. Tomohiro Mizutani
  8. Hans Clevers
  9. Keith R Johnson
  10. Kurt W Fisher
  11. Robert E Lewis
(2021)
KSR1-and ERK-dependent translational regulation of the epithelial-to-mesenchymal transition
eLife 10:e66608.
https://doi.org/10.7554/eLife.66608
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Abstract

The epithelial-to-mesenchymal transition (EMT) is considered a transcriptional process that induces a switch in cells from a polarized state to a migratory phenotype. Here we show that KSR1 and ERK promote EMT-like phenotype through the preferential translation of Epithelial-Stromal Interaction 1 (EPSTI1), which is required to induce the switch from E- to N-cadherin and coordinate migratory and invasive behavior. EPSTI1 is overexpressed in human colorectal cancer (CRC) cells. Disruption of KSR1 or EPSTI1 significantly impairs cell migration and invasion in vitro, and reverses EMT-like phenotype, in part, by decreasing the expression of N-cadherin and the transcriptional repressors of E-cadherin expression, ZEB1 and Slug. In CRC cells lacking KSR1, ectopic EPSTI1 expression restored the E- to N-cadherin switch, migration, invasion, and anchorage-independent growth. KSR1-dependent induction of EMT-like phenotype via selective translation of mRNAs reveals its underappreciated role in remodeling the translational landscape of CRC cells to promote their migratory and invasive behavior.

Data availability

The high-throughput sequencing data have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE164492).

The following data sets were generated

Article and author information

Author details

  1. Chaitra Rao

    Eppley Institute, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2834-7458

  2. Danielle E Frodyma

    Eppley Institute, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Siddesh Southekal

    Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Robert A Svoboda

    Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Adrian R Black

    Eppley Institute, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Chittibabu Guda

    Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Tomohiro Mizutani

    Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.

  8. Hans Clevers

    Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.

  9. Keith R Johnson

    Department of Oral Biology, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Kurt W Fisher

    Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    The authors declare that no competing interests exist.

  11. Robert E Lewis

    Eppley Cancer Institute, University of Nebraska Medical Center, Omaha, United States
    For correspondence
    rlewis@unmc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3616-2971

Funding

Nebraska center for Molecular Target Discovery and Drug Development (P20 GM121316)

  • Robert E Lewis

Fred and Pamela Buffet Cancer Support Grant (P30 CA036727)

  • Robert E Lewis

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Nahum Sonenberg, McGill University, Canada

Version history

  1. Received: January 16, 2021
  2. Accepted: May 9, 2021
  3. Accepted Manuscript published: May 10, 2021 (version 1)
  4. Version of Record published: June 11, 2021 (version 2)
  5. Version of Record updated: May 7, 2024 (version 3)

Copyright

© 2021, Rao 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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  1. Chaitra Rao
  2. Danielle E Frodyma
  3. Siddesh Southekal
  4. Robert A Svoboda
  5. Adrian R Black
  6. Chittibabu Guda
  7. Tomohiro Mizutani
  8. Hans Clevers
  9. Keith R Johnson
  10. Kurt W Fisher
  11. Robert E Lewis
(2021)
KSR1-and ERK-dependent translational regulation of the epithelial-to-mesenchymal transition
eLife 10:e66608.
https://doi.org/10.7554/eLife.66608

Share this article

https://doi.org/10.7554/eLife.66608

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