CYP24A1 Inhibition Facilitates the Antiproliferative Effect of 1,25(OH)(2)D-3 Through Downregulation of the WNT/-Catenin Pathway and Methylation-Mediated Regulation of CYP24A1 in Colorectal Cancer Cells

摘要

CYP24A1 is overexpressed in colorectal cancer, and the reason for the dysregulation of CYP24A1 in colorectal cancer is still unknown. In the present study, experiments were designed to test whether CYP24A1 inhibition facilitated the antiproliferative effect of 1,25(OH)(2)D-3. In addition, the role of methylation in the regulation of CYP24A1 expression in human colorectal cancer was investigated. The expression of CYP24A1 in SW480 and Caco2 colorectal cancer cells was inhibited by RNAi. CYP24A1 inhibition significantly increased the antiproliferative effects of 1,25(OH)(2)D-3 in SW480 cells compared with 1,25(OH)(2)D-3 treatment alone (16.78%+/- 2.08% vs. 33.53%+/- 2.47%, p&0.05). In addition, CYP24A1 inhibition sensitized Caco2 cells to 1,25(OH)(2)D-3. We also found that CYP24A1 inhibition induced -catenin to translocate from the nucleus to the plasma membrane in SW480 cells and enhanced the inhibitory effect of 1,25(OH)(2)D-3 on C-myc. Furthermore, CYP24A1 mRNA expression in Caco2 cells was increased after demethylation treatment, and the expression of CYP24A1 induced by 1,25(OH)(2)D-3 was significantly higher in cells treated with 5-aza-2-deoxycytidine (DAC) than in an untreated group. In conclusion, inhibition of CYP24A1 expression enhances the antitumor effect of 1,25(OH)(2)D-3 in colorectal cancer, and DNA methylation is involved in the regulation of CYP24A1 expression in a cell-dependent manner.