Sox17 and Sox4 differentially regulate beta-catenin/TCF activity and proliferation of colon carcinoma cells

The canonical Wnt-pathway is necessary for gut epithelial cell proliferation and its aberrant activation causes intestinal neoplasia. We report a novel mechanism by which the Sox family of transcription factors regulates the canonical Wnt signaling pathway. We find that some Sox proteins antagonize while others enhance beta-catenin/TCF activity. Sox17, which is expressed in normal gut epithelium but is reduced in intestinal neoplasias, is antagonistic to Wnt signaling. When over-expressed in SW480 colon carcinoma cells, Sox17 represses beta-catenin/TCF activity in a dose-dependent manner and inhibits proliferation. In contrast, Sox4 is expressed in a mutually exclusive domain to Sox17 in normal and neoplastic gut tissue and gain- and loss-of-function studies demonstrate that Sox4 enhances beta-catenin/TCF activity and proliferation of SW480 cells. In addition to binding beta-catenin, both SOX17 and SOX4 physically interact with TCF/LEF family members via their respective HMG box domains. Gain- and loss-of-function experiments suggest that the interaction of SOX proteins with beta-catenin and TCF/LEF proteins regulates their stability. In particular, SOX17 promotes degradation of both beta-catenin and TCF proteins via a non-canonical, GSK3beta-independent mechanism that can be blocked by proteasome inhibitors. In contrast, SOX4 may function to stabilize beta-catenin protein. These findings indicate that SOX proteins can act as both antagonists and agonists of beta-catenin/TCF activity, and this mechanism may regulate Wnt signaling responses in many developmental and disease contexts.