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SALL2, 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 SALL2 in CRC. Immunohistochemical analysis revealed that SALL2 is present in the epithelium and stroma of normal colon tissue but is significantly downregulated in adenomas, carcinomas, and CRC cell lines. Reduced SALL2 expression was associated with elevated levels of active \u03b2-catenin and poorer overall patient survival. Functional assays demonstrated that SALL2 transcriptionally activates AXIN2, a key negative regulator of the Wnt\/\u03b2-catenin pathway. Chromatin immunoprecipitation and promoter-reporter assays confirmed SALL2 binding to the AXIN2 proximal promoter and enhanced promoter activity. Furthermore, SALL2 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 SALL2 as a negative regulator of Wnt\/\u03b2-catenin signaling and support its potential as a prognostic biomarker and therapeutic target in colorectal cancer.<\/jats:p>","DOI":"10.3390\/ijms26167896","type":"journal-article","created":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T16:09:55Z","timestamp":1755274195000},"page":"7896","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["SALL2-Mediated Suppression of WNT Signaling Through Transcriptional Control of AXIN2 in Colorectal Cancer Cells"],"prefix":"10.3390","volume":"26","author":[{"given":"Aracelly","family":"Quiroz","sequence":"first","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular, Facultad de Ciencias Biol\u00f3gicas, Universidad de Concepci\u00f3n, Concepci\u00f3n 4070409, Chile"},{"name":"Laboratorio de Transducci\u00f3n de Se\u00f1ales y C\u00e1ncer, Facultad de Ciencias Biol\u00f3gicas, Universidad de Concepci\u00f3n, Concepci\u00f3n 4070409, Chile"},{"name":"Departamento de Especialidades, Facultad de Medicina, Universidad de Concepci\u00f3n, Concepci\u00f3n 4070409, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1196-1282","authenticated-orcid":false,"given":"Emilia","family":"Escalona","sequence":"additional","affiliation":[{"name":"MARLab, Instituto de Ciencias Biom\u00e9dicas, Facultad de Ciencias de la Salud, Universidad Aut\u00f3noma de Chile, Talca 3460000, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6245-2622","authenticated-orcid":false,"given":"Carlos","family":"Farkas","sequence":"additional","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n en Ciencias Biom\u00e9dicas, Departamento de Ciencias B\u00e1sicas y Morfolog\u00eda, Facultad de Medicina, Universidad Cat\u00f3lica de la Sant\u00edsima Concepci\u00f3n, Concepci\u00f3n 4030000, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5470-5792","authenticated-orcid":false,"given":"Diego","family":"Ben\u00edtez-Riquelme","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular, Facultad de Ciencias Biol\u00f3gicas, Universidad de Concepci\u00f3n, Concepci\u00f3n 4070409, Chile"},{"name":"Laboratorio de Transducci\u00f3n de Se\u00f1ales y C\u00e1ncer, Facultad de Ciencias Biol\u00f3gicas, Universidad de Concepci\u00f3n, Concepci\u00f3n 4070409, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paulina","family":"Sep\u00falveda","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular, Facultad de Ciencias Biol\u00f3gicas, Universidad de Concepci\u00f3n, Concepci\u00f3n 4070409, Chile"},{"name":"Laboratorio de Transducci\u00f3n de Se\u00f1ales y C\u00e1ncer, Facultad de 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C\u00e1ncer, Facultad de Ciencias Biol\u00f3gicas, Universidad de Concepci\u00f3n, Concepci\u00f3n 4070409, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolina","family":"Delgado","sequence":"additional","affiliation":[{"name":"Departamento de Especialidades, Facultad de Medicina, Universidad de Concepci\u00f3n, Concepci\u00f3n 4070409, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0993-8794","authenticated-orcid":false,"given":"Mat\u00edas I.","family":"Hepp","sequence":"additional","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n en Ciencias Biom\u00e9dicas, Departamento de Ciencias B\u00e1sicas y Morfolog\u00eda, Facultad de Medicina, Universidad Cat\u00f3lica de la Sant\u00edsima Concepci\u00f3n, Concepci\u00f3n 4030000, 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