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

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.DOI: http://dx.doi.org/10.7554/eLife.23242.001

SUV39H2 epigenetic silencing controls fate conversion of epidermal stem and progenitor cells

“…2, B and C ; and Table S1 ). In contrast and notably, expression of typical growth-promoting and transforming Wnt coactivators such as Bcl9 ( Mani et al, 2009 ), the skin tumor promoter Tcf7L1 ( Ku et al, 2017 ), Wnt antagonists such as APC2, a component of the destruction complex targeting β-catenin, and DKK4 were down-regulated (up to 3.5-fold). In support of Wnt signaling promoting premature cell cycle exit of progenitor cells, pro-proliferative gene products implicated in cell cycle progression were down-regulated (up to 16-fold).…”

Systems biology analysis identifies TCF7L1 as a key regulator of metastasis in Ewing sarcoma

“…In cancer, the role of TCF7L1 remains poorly understood, and appears to be cell-type specific. For example, TCF7L1 expression has been linked to promotion of cell proliferation and tumor growth and an increase of sphere formation in breast cancer 25 , colorectal cancer 26 and skin squamous cell carcinoma 28 . In contrast, it has been shown that ectopic expression of TCF7L1 inhibits self-renewal of liver cancer stem cells 24 , which are believed to play a prominent role in tumor relapse and metastasis 37 , thus highlighting a potential role of TCF7L1 in the stemness-metastasis axis that strongly depends on the cellular context.…”

“…Little is known about the precise cellular function of TCF7L1 in cancer. However, prior reports suggested that it may have either oncogenic or tumor suppressor properties depending on the cellular context [24][25][26][27][28] . To explore its potential role in EwS, we first analyzed the TCF7L1 expression pattern across 18 cancer entities using publicly available microarray data from the Cancer Cell Line Encyclopedia (CCLE) 29 and from an own study that compiled well-curated microarray data from the same cancer entities 30 .…”

Wnt Signaling Pathways in Keratinocyte Carcinomas

“…A recent study provided evidence for a tumor-promoting role of TCF7L1 in skin. Overexpression of TCF7L1 increased tumor incidence, promoted tumor growth, and enhanced migration independent of β-catenin [158]. In addition to TCF7L1, Wnt genes are also commonly dysregulated in diverse tumor cells, including prostate, ovarian, colon, and skin cancers [159,160,161,162].…”