Suppression of Colonic Polyposis by Homeoprotein CDX2 through its Nontranscriptional Function that Stabilizes p27Kip1

Caudal-related homeoprotein CDX2 is expressed in intestinal epithelial cells, in which it is essential for their development and differentiation. A tumor suppressor function is suggested by evidence that CDX2 levels are decreased in human colon cancer specimens and that an inactivating mutation of Cdx2 in Apc(Delta 716) mice markedly increases the incidence of colonic polyps. In this study, we investigated roles for transcriptional and nontranscriptional functions of CDX2 in suppression of colonic tumorigenesis. Mutagenic analysis of CDX2 revealed that loss of function stabilizes CDK inhibitor p27(Kip1) by a nontranscriptional but homeodomain-dependent mechanism that inhibits cyclin E-CDK2 activity and blocks G0/G1-S progression in colon cancer cells. p27(Kip1) stabilization was mediated by an inhibition of ubiquitylation-dependent proteolysis associated with decreased phosphorylation of Thr187 in p27(Kip1). siRNA-mediated knockdown of p27(Kip1) relieved the decrease in cyclin E-CDK2 activity and S-phase cell fraction elicited by CDX2 expression. Together, these results implicate a nontranscriptional function of CDX2 in tumor suppression mediated by p27(Kip1) stabilization. Up to approximately 75% of low-CDX2 human colon cancer lesions show reduced levels of p27(Kip1), whereas approximately 68% of high-CDX2 lesions retain expression of p27(Kip1). These results show that low levels of CDX2 accelerate colon tumorigenesis by reducing p27(Kip1) levels. Cancer Res; 71(2); 593-602. (C) 2011 AACR.