Mutations in components of the Wnt/β-catenin signaling pathway are highly prevalent in colorectal cancers (CRCs). These mutations deregulate expression of genes controlled by T-cell factor (TCF) transcription factors. While the 4 TCF family members are expressed in CRCs, the number of known targets regulated by TCF7L1 is limited. The aim of this study was to determine the role of TCF7L1 in CRC and to identify direct target genes regulated by this transcription factor.Methods:
TCF7L1 expression in the HCT116 and SW480 CRC cell lines was knocked down using lentivirus encoding TCF7L1-specific shRNAs. Standard proliferation assays, cell cycle analysis, and tumor xenograft assays were used to assess TCF7L1-depleted cells. Microarray analysis was used to identify Dickkopf-4 (DKK4) as a potential direct TCF7L1 target. Luciferase reporter assays and chromatin immunoprecipitation assays were used to determine whether DKK4 was directly regulated by TCF7L1.Results:
Knocking down TCF7L1 expression in HCT116 and SW480 cells compromised cellular proliferation by slowing progression through the cell cycle. TCF7L1-depleted cells displayed reduced tumorigenic potential when implanted into the flanks of immunocompromised mice. Microarray analysis of TCF7L1-depleted cells identified 314 differentially expressed genes, including DKK4, which encodes a known negative regulator of Wnt/β-catenin signaling and the cell cycle. We found that TCF7L1 assembles a CtBP/HDAC1 complex on the DKK4 promoter to repress DKK4 expression.Conclusions:
The TCF family member TCF7L1 represses DKK4 expression to promote CRC cell proliferation and tumorigenesis. These findings suggest that TCF7L1 and DKK4 are potential therapeutic targets to develop novel therapeutics to treat individuals suffering from colorectal cancer.