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.
Article and author information
Author details
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.
Reviewing Editor
- Valerie Horsley, Yale University, United States
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).
Version history
- Received: November 12, 2016
- Accepted: April 29, 2017
- Accepted Manuscript published: May 3, 2017 (version 1)
- 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
-
- 1,678
- views
-
- 364
- downloads
-
- 17
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
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)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
TCF7L1 promotes skin tumorigenesis independently of β-catenin through induction of LCN2
eLife 6:e23242.
https://doi.org/10.7554/eLife.23242
Further reading
-
- Cancer Biology
- Cell Biology
Rapid recovery of proteasome activity may contribute to intrinsic and acquired resistance to FDA-approved proteasome inhibitors. Previous studies have demonstrated that the expression of proteasome genes in cells treated with sub-lethal concentrations of proteasome inhibitors is upregulated by the transcription factor Nrf1 (NFE2L1), which is activated by a DDI2 protease. Here, we demonstrate that the recovery of proteasome activity is DDI2-independent and occurs before transcription of proteasomal genes is upregulated but requires protein translation. Thus, mammalian cells possess an additional DDI2 and transcription-independent pathway for the rapid recovery of proteasome activity after proteasome inhibition.
-
- Cancer Biology
- Cell Biology
Collective cell migration is fundamental for the development of organisms and in the adult, for tissue regeneration and in pathological conditions such as cancer. Migration as a coherent group requires the maintenance of cell-cell interactions, while contact inhibition of locomotion (CIL), a local repulsive force, can propel the group forward. Here we show that the cell-cell interaction molecule, N-cadherin, regulates both adhesion and repulsion processes during rat Schwann cell (SC) collective migration, which is required for peripheral nerve regeneration. However, distinct from its role in cell-cell adhesion, the repulsion process is independent of N-cadherin trans-homodimerisation and the associated adherens junction complex. Rather, the extracellular domain of N-cadherin is required to present the repulsive Slit2/Slit3 signal at the cell-surface. Inhibiting Slit2/Slit3 signalling inhibits CIL and subsequently collective Schwann cell migration, resulting in adherent, nonmigratory cell clusters. Moreover, analysis of ex vivo explants from mice following sciatic nerve injury showed that inhibition of Slit2 decreased Schwann cell collective migration and increased clustering of Schwann cells within the nerve bridge. These findings provide insight into how opposing signals can mediate collective cell migration and how CIL pathways are promising targets for inhibiting pathological cell migration.
