VDR activity is differentially affected by Hic-5 in prostate cancer and stromal cells.
Patients with prostate cancer treated with androgen deprivation therapy (ADT) eventually develop castrate-resistant prostate cancer (CRPC). 1,25-Dihydroxyvitamin D3 (1,25D3/calcitriol) is a potential adjuvant therapy that confers antiproliferative and pro-differentiation effects in vitro, but has had mixed results in clinical trials. The impact of the tumor microenvironment on 1,25D3 therapy in patients with CRPC has not been assessed. Transforming growth factor β (TGFβ), which is associated with the development of tumorigenic "reactive stroma" in prostate cancer, induced vitamin D3 receptor (VDR) expression in the human WPMY-1 prostate stromal cell line. Similarly, TGFβ enhanced 1,25D3-induced upregulation of CYP24A1, which metabolizes 1,25D3 and thereby limits VDR activity. Ablation of Hic-5, a TGFβ-inducible nuclear receptor coregulator, inhibited basal VDR expression, 1,25D3-induced CYP24A1 expression and metabolism of 1,25D3 and TGFβ-enhanced CYP24A1 expression. A Hic-5-responsive sequence was identified upstream (392-451 bp) of the CYP24A1 transcription start site that is occupied by VDR only in the presence of Hic-5. Ectopic expression of Hic-5 sensitized LNCaP prostate tumor cells to growth-inhibitory effects of 1,25D3 independent of CYP24A1. The sensitivity of Hic-5-expressing LNCaP cells to 1,25D3-induced growth inhibition was accentuated in coculture with Hic-5-ablated WPMY-1 cells. Therefore, these findings indicate that the search for mechanisms to sensitize prostate cancer cells to the antiproliferative effects of VDR ligands needs to account for the impact of VDR activity in the tumor microenvironment.


CONCLUSIONS
Hic-5 acts as a coregulator with distinct effects on VDR transactivation, in prostate cancer and stromal cells, and may exert diverse effects on adjuvant therapy designed to exploit VDR activity in prostate cancer.
Departments of Molecular Genetics and Developmental Biology and.
Joshua D
JD
Solomon
Pharmacology and Chemical Biology;
Marjet D
MD
Heitzer
Pharmacology and Chemical Biology;
Teresa T
TT
Liu
Clinical Pharmacology Analytical Facility;
Jan H
JH
Beumer
Clinical Pharmacology Analytical Facility;
Robert A
RA
Parise
Biostatistics Facility, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania; and.
Daniel P
DP
Normolle
The Basil Hetzel Institute for Translational Health Research, University of Adelaide, South Australia, Australia.
Damien A
DA
Leach
The Basil Hetzel Institute for Translational Health Research, University of Adelaide, South Australia, Australia.
Grant
G
Buchanan
Departments of Molecular Genetics and Developmental Biology and Pharmacology and Chemical Biology; dod1@pitt.edu.
Donald B
DB
DeFranco
D000728:Androgens / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D002762:Cholecalciferol / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism*; D024363:Transcription Initiation Site / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics / Q000378:metabolism
C116777:1,25-dihydroxy-16,23-diene vitamin D3; D000728:Androgens; D004268:DNA-Binding Proteins; D018167:Receptors, Calcitriol; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D002762:Cholecalciferol; D065668:Vitamin D3 24-Hydroxylase