Our data demonstrate that SATB2 is highly expressed in colon cancer cell lines, and primary CRC tissues, and but not in human normal colon epithelial cells and human normal colon, (ii) overexpression of SATB2 can transform human normal colon epithelial cells to progenitor-like cells/CSCs, (iii) inhibition of SATB2 by shRNA attenuates CRC cell proliferation, colony formation and EMT, and (iv) SATB2 expression correlates with nuclear β-catenin expression, and silencing of SATB2 inhibits TCF/LEF activity and its targets. Here, SATB2 is linked to malignant colon neoplasm.