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

Amy T Ku,Abdul H Diwan,Daniel N Cohen,Gloria Garcia,Malgorzata Borowiak,Diep Le,Kenneth Y Tsai,Vida Chitsazzadeh,Qi Miao,Jeffrey M Howard,Christine N Rodriguez,Ajay S Rao,Timothy M Shaver,Diane Yang,Hoang Nguyen

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.

Highlights

Cancer cells have many characteristics in common with stem cells (Beck and Blanpain, 2013)
In the UV-induced mouse model of skin squamous cell carcinoma (SCC), where papillomas and SCC develop from skin that is chronically exposed to UV radiation, increased expression of TCF7L1 was observed in 2 out of 4 cases of skin SCC examined (Figure 1B)
TCF7L1 is an embryonic stem cell signature gene that is upregulated in multiple aggressive cancer types, including breast cancer, glioblastoma, and bladder carcinoma (Ben-Porath et al, 2008)

Summary

Introduction

Cancer cells have many characteristics in common with stem cells (Beck and Blanpain, 2013). Cancer Biology Cell Biology found to be highly enriched (Ben-Porath et al, 2008). One such ES cell signature gene enriched in aggressive tumors is TCF7L1 ( known as TCF3). TCF7L1 is a member of the LEF/TCF (lymphoid enhancer factor/T cell factor) family of transcription factors, which act as DNA binding partners for the WNT mediator b-catenin (Korinek et al, 1998). In response to canonical WNT signaling, b-catenin is translocated to the nucleus and partners with LEF/TCF members to activate transcription of WNT target genes (Behrens et al, 1996; Molenaar et al, 1996; van de Wetering et al, 1997). In the absence of WNT ligands, LEF/TCF binds to Groucho/TLE co-repressors to inhibit transcription of WNT target genes (Cavallo et al, 1998; Roose et al, 1998)

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