Overexpressed in lung cancer 1 (OLC1) is a potential oncogene overexpressed in human lung cancer and in other types of malignant tumor. The elevated expression of OLC1 contributes to tumor genesis and progression. However, the mechanisms regulating the expression of OLC1 remain unclear. In the present study, using lung and esophageal cancer cell lines, it was demonstrated that OLC1 was a short-lived, cell cycle-dependent protein regulated through the anaphase-promoting complex/cyclosome (APC/c)-ubiquitin pathway by directly interacting with the APC2 subunit. Through the action of two co activator proteins, cadherin 1 (Cdh1) and cell-division cycle protein 20 (Cdc20), the OLC1 protein was ubiquitinated and degraded. Following treatment with a proteasome inhibitor, OLC1 protein levels were elevated. Inversely, the upregulation of Cdh1 and Cdc20 facilitated OLC1 degradation. By inducing point mutations of the assumed degradation motif of OLC1, it was revealed that an intact destruction (D)-box was necessary. As expected, the D-box-mutated OLC1 exhibited a higher capacity for promoting cell growth and clone formation. Collectively, these findings indicate that the expression of the candidate oncogene OLC1 is cell cycle-dependent and is regulated by an APC/c mediated ubiquitin-proteasome pathway.