SALL2-Mediated Suppression of WNT Signaling Through Transcriptional Control of AXIN2 in Colorectal Cancer Cells

Colorectal cancer (CRC) remains the second leading cause of cancer-related mortality worldwide, with aberrant activation of the Wnt/β-catenin signaling pathway constituting a key driver of tumorigenesis. <i>SALL2</i>, a zinc finger transcription factor deregulated in various cancers, has been implicated in Wnt signaling regulation through its Xenopus ortholog; however, its role in human CRC remains unclear. In this study, we investigated the expression and function of <i>SALL2</i> in CRC. Immunohistochemical analysis revealed that <i>SALL2</i> is present in the epithelium and stroma of normal colon tissue but is significantly downregulated in adenomas, carcinomas, and CRC cell lines. Reduced <i>SALL2</i> expression was associated with elevated levels of active β-catenin and poorer overall patient survival. Functional assays demonstrated that <i>SALL2</i> transcriptionally activates <i>AXIN2</i>, a key negative regulator of the Wnt/β-catenin pathway. Chromatin immunoprecipitation and promoter-reporter assays confirmed <i>SALL2</i> binding to the <i>AXIN2</i> proximal promoter and enhanced promoter activity. Furthermore, <i>SALL2</i> expression potentiated the pro-apoptotic effects of the Wnt pathway inhibitor XAV939 in CRC cells, suggesting a role in sensitizing cells to Wnt-targeted therapies. Collectively, these findings identify <i>SALL2</i> as a negative regulator of Wnt/β-catenin signaling and support its potential as a prognostic biomarker and therapeutic target in colorectal cancer.