TCF7L1 promotes skin tumorigenesis independently of β-catenin through induction of LCN2

  1. Amy T Ku
  2. Timothy M Shaver
  3. Ajay S Rao
  4. Jeffrey M Howard
  5. Christine N Rodriguez
  6. Qi Miao
  7. Gloria Garcia
  8. Diep Le
  9. Diane Yang
  10. Malgorzata Borowiak
  11. Daniel N Cohen
  12. Vida Chitsazzadeh
  13. Abdul H Diwan
  14. Kenneth Y Tsai
  15. Hoang Nguyen  Is a corresponding author
  1. Baylor College of Medicine, United States
  2. University of Texas MD Anderson Cancer Center, United States
  3. Moffitt Cancer Center, United States

Abstract

The transcription factor TCF7L1 is an embryonic stem cell signature gene that is upregulated in multiple aggressive cancer types, but its role in skin tumorigenesis has not yet been defined. Here we document TCF7L1 upregulation in skin squamous cell carcinoma (SCC) and demonstrate that TCF7L1 overexpression increases tumor incidence, tumor multiplicity, and malignant progression in the chemically induced mouse model of skin SCC. Additionally, we show that downregulation of TCF7L1 and its paralogue TCF7L2 reduces tumor growth in a xenograft model of human skin SCC. Using separation-of-function mutants, we show that TCF7L1 promotes tumor growth, enhances cell migration, and overrides oncogenic RAS-induced senescence independently of its interaction with β-catenin. Through transcriptome profiling and combined gain- and loss-of-function studies, we identified LCN2 as a major downstream effector of TCF7L1 that drives tumor growth. Our findings establish a tumor-promoting role for TCF7L1 in skin and elucidate the mechanisms underlying its tumorigenic capacity.

Article and author information

Author details

  1. Amy T Ku

    Stem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Timothy M Shaver

    Stem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ajay S Rao

    Stem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jeffrey M Howard

    Stem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Christine N Rodriguez

    Stem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Qi Miao

    Stem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Gloria Garcia

    Stem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Diep Le

    Stem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Diane Yang

    Stem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Malgorzata Borowiak

    Stem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Daniel N Cohen

    Department of Pathology and Immunology, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Vida Chitsazzadeh

    Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Abdul H Diwan

    Department of Dermatology, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Kenneth Y Tsai

    Anatomic Pathology and Tumor Biology, Moffitt Cancer Center, Tampa, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Hoang Nguyen

    Stem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States
    For correspondence
    hoangn@bcm.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1091-7483

Funding

Cancer Prevention and Research Institute of Texas (RP110153)

  • Hoang Nguyen

Cancer Prevention and Research Institute of Texas (RP101499)

  • Jeffrey M Howard

National Institutes of Health (T32-HL092332-07)

  • Jeffrey M Howard

National Institutes of Health (T32HL92332)

  • Amy T Ku

National Institutes of Health (T32GM088129)

  • Amy T Ku

National Institutes of Health (7R01CA194617)

  • Kenneth Y Tsai

National Institutes of Health (R01 CA194062)

  • Kenneth Y Tsai

T . Boone Pickens Endowment

  • Kenneth Y Tsai

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

Ethics

Animal experimentation: All mice were maintained in the AALAC-accredited animal facilities at Baylor College of Medicine and MD Anderson and all mouse experiments were conducted according to protocols approved by committees at Baylor College of Medicine (AN-4907) and MD Anderson (ACUF00001396-RN00).

Reviewing Editor

  1. Valerie Horsley, Yale University, United States

Publication history

  1. Received: November 12, 2016
  2. Accepted: April 29, 2017
  3. Accepted Manuscript published: May 3, 2017 (version 1)
  4. Version of Record published: May 19, 2017 (version 2)

Copyright

© 2017, Ku 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. Amy T Ku
  2. Timothy M Shaver
  3. Ajay S Rao
  4. Jeffrey M Howard
  5. Christine N Rodriguez
  6. Qi Miao
  7. Gloria Garcia
  8. Diep Le
  9. Diane Yang
  10. Malgorzata Borowiak
  11. Daniel N Cohen
  12. Vida Chitsazzadeh
  13. Abdul H Diwan
  14. Kenneth Y Tsai
  15. Hoang Nguyen
(2017)
TCF7L1 promotes skin tumorigenesis independently of β-catenin through induction of LCN2
eLife 6:e23242.
https://doi.org/10.7554/eLife.23242

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