TY - JOUR
T1 - Altered VDR-mediated transcriptional activity in prostate cancer stroma
AU - Hidalgo, Alejandro A.
AU - Paredes, Roberto
AU - Garcia, Victor M.
AU - Flynn, Geraldine
AU - Johnson, Candace S.
AU - Trump, Donald L.
AU - Onate, Sergio A.
N1 - Funding Information:
This research was supported in part by the American Cancer Society (RSG-01-243-01). The authors would like to acknowledge the support from the Translational Research Tissue Resource and the Histology/Pathology core facilities at the Roswell Park Cancer Institute for providing prostate tissue from the organ donor program and immunohistochemistry for VDR immunostaining.
PY - 2007/3
Y1 - 2007/3
N2 - The 1α,25-dihydroxy-vitamin D3 (1α,25(OH)2D3) mediated gene transcription in primary cultures of human prostate cells was analyzed using an adenoviral luciferase expression reporter under the control of the 25-hydroxy-vitamin D3-24-hydroxylase (CYP24) gene promoter. Stromal cells isolated from benign and malignant associated stroma (BAS and CAS) of a human clinical sample have been determined to contain similar levels of functional 1α,25(OH)2D3 receptor (VDR). However, VDR-mediated reporter activity of the luciferase reporter has been found to be limited 7-9-fold in CAS compared to 14-16-fold in BAS. Chromatin immunoprecipitation (ChIP) assays indicate that in the absence of added ligand VDR interact with the silencing mediator for retinoid and thyroid hormone (SMRT) corepressor in both cell types, with higher recruitment in CAS as compared to BAS cells. In the presence of added ligand, VDR in CAS cells exhibited decreased ligand-inducible DNA binding activity, altered recruitment of coregulators SRC-1 and CBP, and increased recruitment of SMRT corepressor, as compared to BAS. Additionally, overexpression of wild-type VDR recovered VDR-mediated transaction of CYP24 luciferase reporter. These results indicate that VDR structure/function and coregulator recruitment to 1α,25(OH)2D3 regulated genes is altered in the CaP stroma microenvironment.
AB - The 1α,25-dihydroxy-vitamin D3 (1α,25(OH)2D3) mediated gene transcription in primary cultures of human prostate cells was analyzed using an adenoviral luciferase expression reporter under the control of the 25-hydroxy-vitamin D3-24-hydroxylase (CYP24) gene promoter. Stromal cells isolated from benign and malignant associated stroma (BAS and CAS) of a human clinical sample have been determined to contain similar levels of functional 1α,25(OH)2D3 receptor (VDR). However, VDR-mediated reporter activity of the luciferase reporter has been found to be limited 7-9-fold in CAS compared to 14-16-fold in BAS. Chromatin immunoprecipitation (ChIP) assays indicate that in the absence of added ligand VDR interact with the silencing mediator for retinoid and thyroid hormone (SMRT) corepressor in both cell types, with higher recruitment in CAS as compared to BAS cells. In the presence of added ligand, VDR in CAS cells exhibited decreased ligand-inducible DNA binding activity, altered recruitment of coregulators SRC-1 and CBP, and increased recruitment of SMRT corepressor, as compared to BAS. Additionally, overexpression of wild-type VDR recovered VDR-mediated transaction of CYP24 luciferase reporter. These results indicate that VDR structure/function and coregulator recruitment to 1α,25(OH)2D3 regulated genes is altered in the CaP stroma microenvironment.
KW - Coactivator
KW - Corepressor
KW - Nuclear receptor
KW - Prostate cancer microenvironment
KW - Prostate cancer stromal cells
KW - Transcriptional regulation
KW - Vitamin D receptor
UR - http://www.scopus.com/inward/record.url?scp=33947105057&partnerID=8YFLogxK
U2 - 10.1016/j.jsbmb.2006.12.072
DO - 10.1016/j.jsbmb.2006.12.072
M3 - Article
C2 - 17368189
AN - SCOPUS:33947105057
VL - 103
SP - 731
EP - 736
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
SN - 0960-0760
IS - 3-5
ER -
