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.
Highlights
A number of genes and encoded proteins participate in the maintenance of stemness and the differentiation of colorectal cancer (CRC) cells [1,2,3]
We provide the first demonstration that Achaete scute-like 2 (Ascl2) acts as a putative transcriptional repressor of caudal type homeobox 2 (CDX2) in CRC cells, with direct implications for intestinal differentiation
Maintaining the stemness of CRC stem cells leads to inhibition of cellular differentiation; there has been a lack of molecular-level evidence of a direct association between these processes [3]
Summary
A number of genes and encoded proteins participate in the maintenance of stemness and the differentiation of colorectal cancer (CRC) cells [1,2,3]. Ascl is over-expressed in colorectal cancer [6, 8, 9], shifting the hierarchy of stem and progenitor cells in liver metastases and results in self-renewal rather than differentiation [9]. Blockade of Ascl expression in HT29 and LS174T cells results in tumor growth arrest via miRNA-302b-mediated inhibition of CRC progenitor cells and induces miR-200 family expression, further promoting epithelial-mesenchymal transition (EMT)-mesenchymalepithelial transition (MET) plasticity via a transcriptional mechanism [10, 11]. Ascl may be a regulatory factor in the maintenance of CRC stem cell
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