Achaete scute-like 2 suppresses CDX2 expression and inhibits intestinal neoplastic epithelial cell differentiation.

// Yangyang Shang 1,* , Qiong Pan 1,* , Lei Chen 1,* , Jun Ye 1 , Xiaoli Zhong 1 , Xiaohuan Li 1 , Linkuan Meng 1 , Jin Guo 1 , Yin Tian 1 , Yonghong He 1 , Wensheng Chen 1 , Zhihong Peng 1 and Rongquan Wang 1 1 Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, P. R. China * These authors have contributed equally to this study Correspondence to: Zhihong Peng , email: // Rongquan Wang, email: // Keywords : Achaete scute-like 2, CDX2, transcriptional regulation, colorectal carcinoma, differentiation Received : March 26, 2015 Accepted : August 13, 2015 Published : August 17, 2015 Abstract The role of Achaete scute-like 2 (Ascl2) in colorectal cancer (CRC) cell differentiation is unknown. LS174T, HT-29 and Caco-2 cells have high Ascl2 expression, while Lovo and SW480 cells have low Ascl2 expression. LS174T and HT-29 cells with Ascl2 knockdown were transfected with caudal type homeobox 2 (CDX2) promoter constructs and used for luciferase assays and chromatin immunoprecipitation (ChIP) assays. Ascl2 knockdown promoted differentiation of CRC cells into a goblet cell phenotype, as determined by increased expression of MUC2, TFF3, and CDX2. Ascl2 knockdown activated CDX2 expression through a transcriptional mechanism via direct binding of Ascl2 to the proximal E-box of the CDX2 promoter. Ascl2 over-expression in Lovo and SW480 cells inhibited a goblet cell phenotype, as determined by reduced CDX2 and MUC2 expression. Inverse correlations between Ascl2 and CDX2, and Ascl2 and MUC2 mRNA levels, as well as Ascl2 and CDX2 protein levels were observed in CRC cancerous samples. This study demonstrates CDX2 repression by Ascl2 and highlights a role for Ascl2 in CRC cell differentiation. These findings suggest that the Ascl2/CDX2 axis may serve as a potential therapeutic target in colorectal cancer.