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Signaling and Regulation

Increased Expression of Corepressors in Aggressive Androgen-Independent Prostate Cancer Cells Results in Loss of 1,25-Dihydroxyvitamin D₃ Responsiveness

Departments of ¹ Urology, ² Chemical Engineering, and ³ Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York

Requests for reprints: Yi-Fen Lee, Department of Urology, University of Rochester, 601 Elmwood Avenue, Box 626, Rochester, NY 14642. Phone: 585-275-9702; Fax: 585-756-4133. E-mail: YiFen_Lee{at}urmc.rochester.edu

Vitamin D has antiproliferative activity in prostate cancer; however, resistance to vitamin D–mediated growth inhibition occurs. To investigate the mechanisms of vitamin D resistance, we screened two prostate cancer sublines of CWR22rv1, CWR22R-1, and CWR22R-2, with differential sensitivity to vitamin D. CWR22R-2 showed less response to the antiproliferative effect of vitamin D than CWR22R-1. The vitamin D receptor (VDR)–mediated transcriptional activity was also decreased in CWR22R-2. We further showed that the DNA-binding ability of VDR was decreased and the amount of NCoR in VDR response element was increased in CWR22R-2. Analysis of VDR-associated protein profiles found higher expression of the corepressors, NCoR1 and SMRT, in CWR22R-2 cells. Treatment with the histone deacetylase inhibitor, trichostatin A, increased vitamin D/VDR transcriptional activity and promoted the antiproliferative effect of vitamin D in CWR22R-2 cells. Targeted down-regulation of NCoR1 and SMRT by small interference RNA was able to restore CWR22R-2 response to vitamin D. Together, we showed that increased NCoR1 and SMRT expression in CWR22R-2 cells resulted in reduced VDR-mediated transcriptional activity and attenuated antiproliferative response to vitamin D. Our data suggest that the integrity of the vitamin D/VDR–mediated signaling pathway is crucial in predicting vitamin D responsiveness and thus provide a rational design to improve vitamin D–based treatment efficacy based on molecular profiles of patients. (Mol Cancer Res 2007;5(9):967–80)