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Inhibition of F-Box Protein p45^SKP2 Expression and Stabilization of Cyclin-Dependent Kinase Inhibitor p27^KIP1 in Vitamin D Analog-Treated Cancer Cells

Departments of Physiology (R.L., T.T.W., J.H.W.) and Medicine (R.L., T.T.W., J.H.W.), McGill University, Montréal, Québec H3G 1Y6, Canada; and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital (W.H.M.), Montréal Centre for Experimental Therapeutics in Cancer (W.H.M., J.H.W.), Montréal, Québec H3T 1E2, Canada

Address all correspondence and requests for reprints to: John H. White, Department of Physiology, McGill University, McIntyre Building, Room 1128, 3655 Drummond Street, Montréal, Québec H3G 1Y6, Canada.

Treatment of cancer cells with 1,25-dihydroxyvitamin D3 [1,25(OH)₂D₃] or its analogs induces growth arrest and expression of the cyclin-dependent kinase inhibitor p27^KIP1. Although 1,25(OH)₂D₃ transiently enhances p27^kip1 gene transcription in some cells, its effects on p27^KIP1 protein levels are generally more gradual and sustained. This suggests that 1,25(OH)₂D₃ treatment may be stabilizing p27^KIP1 protein, which is sensitive to modification by the SCF^SKP2 protein ubiquitin ligase and proteosomal degradation. Here, we show that treatment of AT-84 head and neck squamous carcinoma cells with the 1,25(OH)₂D₃ analog EB1089 increases p27^KIP1 protein levels without significantly affecting expression of its mRNA. EB1089 treatment repressed expression of mRNAs encoding the F-box protein p45^SKP2, a marker of poor head and neck cancer prognosis, and the cyclin kinase subunit CKS1, which is essential for targeting p45^SKP2 to p27^KIP1. This coincided with a reduction of total p45^SKP2 protein, and p45^SKP2 associated with p27^KIP1. Consistent with these findings, turnover of p27^KIP1 protein was strongly inhibited in the presence of EB1089. A similar reduction in p45^SKP2 expression and stabilization of p27^KIP1 protein was observed in 1,25(OH)₂D₃-sensitive UF-1 promyelocytic leukemia cells, which also respond by transiently increasing p27^kip1 gene transcription. Our results reveal that 1,25(OH)₂D₃ analogs increase levels of p27^KIP1 in different cell types by inhibiting expression of SCF^SKP2 subunits and reducing turnover of p27^KIP1 protein.

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