1. Cancer Biology
  2. Cell Biology
Download icon

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
Research Article
  • Cited 11
  • Views 1,459
  • Annotations
Cite this article as: eLife 2017;6:e23242 doi: 10.7554/eLife.23242

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.

Metrics

  • 1,459
    Page views
  • 328
    Downloads
  • 11
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cancer Biology
    2. Ecology
    Daniel Garcia-Souto et al.
    Short Report

    Clonally transmissible cancers are tumour lineages that are transmitted between individuals via the transfer of living cancer cells. In marine bivalves, leukaemia-like transmissible cancers, called hemic neoplasia (HN), have demonstrated the ability to infect individuals from different species. We performed whole-genome sequencing in eight warty venus clams that were diagnosed with HN, from two sampling points located more than 1000 nautical miles away in the Atlantic Ocean and the Mediterranean Sea Coasts of Spain. Mitochondrial genome sequencing analysis from neoplastic animals revealed the coexistence of haplotypes from two different clam species. Phylogenies estimated from mitochondrial and nuclear markers confirmed this leukaemia originated in striped venus clams and later transmitted to clams of the species warty venus, in which it survives as a contagious cancer. The analysis of mitochondrial and nuclear gene sequences supports all studied tumours belong to a single neoplastic lineage that spreads in the Seas of Southern Europe.

    1. Cancer Biology
    2. Cell Biology
    Alejandro La Greca et al.
    Research Article

    Estrogen (E2) and Progesterone (Pg), via their specific receptors (ERalpha and PR), are major determinants in the development and progression of endometrial carcinomas, However, their precise mechanism of action and the role of other transcription factors involved are not entirely clear. Using Ishikawa endometrial cancer cells, we report that E2 treatment exposes a set of progestin-dependent PR binding sites which include both E2 and progestin target genes. ChIP-seq results from hormone-treated cells revealed a non-random distribution of PAX2 binding in the vicinity of these estrogen-promoted PR sites. Altered expression of hormone regulated genes in PAX2 knockdown cells suggests a role for PAX2 in fine-tuning ERalpha and PR interplay in transcriptional regulation. Analysis of long-range interactions by Hi-C coupled with ATAC-seq data showed that these regions, that we call 'progestin control regions' (PgCRs), exhibited an open chromatin state even before hormone exposure and were non-randomly associated with regulated genes. Nearly 20% of genes potentially influenced by PgCRs were found to be altered during progression of endometrial cancer. Our findings suggest that endometrial response to progestins in differentiated endometrial tumor cells results in part from binding of PR together with PAX2 to accessible chromatin regions. What maintains these regions open remains to be studied.