The intestinal stem cell regulating gene ASCL2 is required for L1-mediated colon cancer progression

Aberrant Wnt/β-catenin signaling is a common event during human colorectal cancer (CRC) development. Previously, we characterized members of the L1 family of cell adhesion receptors as targets of β-catenin-LEF1/TCF transactivation that are expressed at the invasive CRC tissue edge. Overexpression of L1 in CRC cells confers enhanced motility, tumorigenesis and liver metastasis. We identified several downstream targets of L1-mediated signaling that are considered key intestinal stem cell signature genes. Here, we investigated the involvement of ASCL2, a Wnt target gene and key determinant of intestinal stem cell state, in L1-mediated CRC progression. In L1 overexpressing CRC cells we found an increase in ASCL2, a decrease in E-cadherin and accumulation of nuclear β-catenin, β-catenin-LEF1/TCF transactivation and target gene expression. The increase in ASCL2 by L1 overexpression enhanced ASCL2 target gene expression, conferred increased motility, tumorigenesis and metastasis, similar to L1 overexpression. Suppression of ASCL2 in cells expressing L1 blocked these tumorigenic properties. In human CRC tissue, ASCL2 was detected in the nuclei of cells at invasive areas of the tumor that also expressed L1. The results suggest that increased ASCL2 expression is a critical step in L1-mediated CRC progression.