The Wnt/B-catenin pathway has been implicated in human cancers. Here, we show that TC1 (C8orf4), a small protein present in vertebrates, functions as a positive regulator of the pathway. TC1 interacts with Chibby (Cby) and thereby enhances the signaling pathway by relieving the antagonistic function of Cby on the B-catenin-mediated transcription. Upon coexpression in mammalian cells, TC1 redistributes from nucleolus to nuclear speckles, where it colocalizes with Cby. TC1 upregulates the expression of B-catenin target genes that are implicated in invasiveness and aggressive behavior of cancers, such as metalloproteinases, laminin ;2, and others. Our data indicate that TC1 is a novel upstream regulator of the Wnt/Bcatenin pathway that enhances aggressive behavior of cancers. (Cancer Res 2006; 66(2): 723-8)

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