Prostate 25-hydroxyvitamin D-1alpha-hydroxylase is up-regulated by suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor.
Prostatic 25-hydroxyvitamin D-1alpha-hydroxylase (1alpha-OHase) is up-regulated by epidermal growth factor (EGF) and down-regulated by 1alpha,25-dihydroxyvitamin D [1alpha,25(OH)2D] at the promoter level in an autocrine/paracrine fashion, suggesting that local production of 1alpha,25(OH)2D could provide an important cell growth regulatory mechanism. Gene expressions depend on the acetylation status of the histone tails of chromatin, which is regulated by histone acetyltransferases and histone deacetylases (HDAC). A number of HDAC inhibitors, including suberolylanilide hydroxamic acid (SAHA), can inhibit tumor growth in vitro and in vivo. Moreover, SAHA increases the expression of genes which modulate cell cycle progression, tumor suppression, differentiation and apoptosis. Therefore, whether SAHA might also regulate 1alpha-OHase activity in PZ-HPV-7 prostate cells was investigated. SAHA at 10 microM up-regulated 1alpha-OHase activity approximately two-fold as analyzed by the formation of 3H-1alpha,25(OH)2D3 from 3H-25-hydroxyvitamin D3 using high performance liquid chromatography. SAHA (10 microM) also stimulated 1alpha-OHase mRNA expression as measured by real-time polymerase chair reaction, and promoter activity determined by luciferase reporter gene assay. The findings suggest that another important action of SAHA may be to up-regulate the expression of the 1alpha-OHase gene that controls the synthesis of 1alpha,25(OH)2D which in turn regulates prostate growth and differentiation in an autocrine/paracrine fashion.
Wang
Lilin
L
Section of Endocrinology, Diabetes and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Persons
Kelly S
KS
Jamieson
Dan
D
Flanagan
John N
JN
Hsu
Hui H
HH
Holick
Michael F
MF
Luo
Z
Z
Sakaki
Toshi
T
Urushino
N
N
Faller
Douglas V
DV
Chen
Tai C
TC
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000096:biosynthesis* / Q000235:genetics; D048708:Cell Growth Processes / Q000187:drug effects; D002461:Cell Line, Transformed; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011467:Prostate / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D000077337:Vorinostat
D006877:Hydroxamic Acids; D012333:RNA, Messenger; D000077337:Vorinostat; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase