Cell-cycle progression is a strictly regulated process, and uncontrolled cell proliferation causes cancer. One of the most critical regulatory mechanisms of cell-cycle progression is the timely degradation of CDK inhibitors. p21 and p27 are CDK inhibitors that are important for the progression from the G0/G1 to S phase. During the early G1 to late G1 phase, p27 is exported from the nucleus to the cytosol and degraded by the KPC pathway. From the late G1 to the S phase boundary, both p21 and p27 are degraded by the SCF^-SKP2 pathway in the nucleus. VCP/p97, which is an AAA-ATPase, participates in a wide variety of cellular processes and is reported to be overexpressed in many types of cancers. However, the role of p97 in the cell cycle progression of cancer cells remains poorly understood. Here, we found that the timely degradation of both p21 and p27 during the G0/G1 to S phase progression was blocked in VCP knockdown or VCP inhibitor-treated MCF-7 human breast cancer cells, and the knockdown of both p21 and p27 reversed the S phase entry defect in VCP inhibitor-treated cells. Moreover, the nuclear export of p27 was blocked in VCP or its co-factor Ufd1 knockdown cells. We further identified the potential nuclear localization sequence (NLS) of VCP, and the addition of wild type VCP, but not the NLS-mutant VCP, restored the nuclear export and degradation of p27 in VCP knockout MCF-7 cells. Importantly, the VCP inhibitor could sensitize the 5-Fu or doxorubicin in killing breast cancer cells. Taken together, the results of our study not only uncover the mechanisms underlying VCP-mediated cell proliferation control but also provide a potential therapeutic option for cancer treatment.