Prostatic 25-hydroxyvitamin D-1alpha-hydroxylase and its implication in prostate cancer.
Evidence suggests that vitamin D may have a protective role for prostate cancer. 1alpha,25-Dihydroxyvitamin D [1alpha,25(OH)(2)D] inhibits growth and induces differentiation of prostate cells. 25-Hydroxyvitamin D-1alpha-hydroxylase [1alpha-OHase], the enzyme that is responsible for the synthesis of 1alpha,25(OH)(2)D, is expressed in cultured prostate cells. We observed a marked decrease in 1alpha-OHase activity in prostate cancer cells, suggesting some defect of the 1alpha-OHase in these cells. To investigate whether the defect was due to dysregulation of the enzyme at the promoter level, a series of deletion constructs of the promoter was synthesized and incorporated upstream into the luciferase reporter gene. Two regions were identified with high basal activity in transfected normal prostate cell line (PZHPV-7), -1100 bp (AN2), and -394 bp (AN5) upstream of ATG start site of the 1alpha-OHase gene. When the reporter gene with either AN2 or AN5 was transfected into prostate cancer cell lines, we observed a lower basal promoter activity in PC-3 cells and DU145 cells than that found in PZHPV-7 cells for both constructs, and a loss of promoter activity in LNCaP cells. Thus, the results suggest that the defect in enzyme activity may result from the decreased promoter activity in prostate cancer cells.
Chen
Tai C
TC
Vitamin D, Skin and Bone Research Laboratory, Division of Endocrinology, Department of Medicine, Boston University Medical Center, Boston, MA, USA. taichen@bu.edu
Wang
Lilin
L
Whitlatch
Lyman W
LW
Flanagan
John N
JN
Holick
Michael F
MF
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism*; D002112:Calcifediol / Q000378:metabolism / Q000494:pharmacology; D002117:Calcitriol / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D017930:Genes, Reporter; D006801:Humans; D008297:Male; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000166:cytology / Q000201:enzymology; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D002112:Calcifediol