Previous studies have shown that decorin expression is significantly reduced in colorectal cancer tissues and cancer cells, and genetic deletion of the decorin gene is sufficient to cause intestinal tumor formation in mice, resulting from a downregulation of p21, p27kip1 and E-Cadherin and an upregulation of β-catenin signaling (Bi et al. Carcinogenesis, 2008). However, the regulation of E-Cadherin by decorin and its implication in cancer formation and metastasis is largely unknown. Using a decorin knockout mouse model (Dcn-/- mice) and manipulated expression of decorin in human colorectal cancer cells we found that E-Cadherin, a protein that regulates cell-cell adhesion, epithelial-mesenchymal transition and metastasis, was almost completely lost in Dcn-/- mouse intestine, and loss of decorin and E-Cadherin accelerated colon cancer cell growth and invasion in Dcn- /- mice. However, increasing decorin expression in colorectal cancer cells attenuated cancer cell malignancy, including inhibition of cancer cell proliferation, promotion of apoptosis, and importantly, attenuation of cancer cell migration. All these changes were linked to the regulation of E-Cadherin by decorin. Moreover, overexpression of decorin upregulated E-Cadherin through increasing of ECadherin protein stability as E-Cadherin mRNA and promoter activity were not affected. Co-immunoprecipitation assay showed a physical binding between decorin and E-Cadherin proteins. Taken together, our results provide direct evidence that decorin-mediated inhibition of colorectal cancer growth and migration is through the interaction with and stabilization of E-Cadherin.