TCF7L1 promotes skin tumorigenesis independently of β-catenin through induction of LCN2
- Baylor College of Medicine, United States
- University of Texas MD Anderson Cancer Center, United States
- 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.
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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).
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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TCF7L1 promotes skin tumorigenesis independently of β-catenin through induction of LCN2
eLife 6:e23242.
https://doi.org/10.7554/eLife.23242
