Abrogated entry into S phase is a common hallmark of cancer cells. Skp2, a subunit of ubiquitin ligase, is critical for regulating the G(1)/S transition. Uncontrolled Skp2 activity is detected frequently in human tumors, often correlated with poor prognosis. Current studies have suggested that the regulation of Skp2 turnover is mediated by another critical ubiquitin ligase, the anaphase-promoting complex (APC), in association with its substrate-specific factor Cdh1. To dissect the potential role of Cdh1/APC in tumorigenesis through the degradation of Skp2, we analyzed the Cdh1/APC-Skp2-p27 axis in colorectal tumorigenesis using a human tumor array and biochemical analyses. Our results show that the percentage of Cdh1- and p27-positive samples in colon cancer tissues was significantly lower than that in adjacent nonmalignant tissue. Conversely, the percentage of Skp2-positive colon cancer samples was significantly higher than that in normal tissue. Furthermore, results from clinicopathological analysis revealed that elevated Cdh1 expression was associated with lower histological grade tumors. In addition, depletion of Cdh1 by RNA interference in nonmalignant colon cells resulted in increased cellular proliferation, whereas knockdown of Skp2 significantly suppressed cancer cell growth. Our result suggests a pathological correlation between Skp2 and Cdh1/APC in colorectal cancer. Thus, Cdh1 may function as a component in tumor suppression via proteolysis of Skp2 in colorectal tumorigenesis and may serve as a prognostic marker in colon cancer patients.