Altered VDR-mediated transcriptional activity in prostate cancer stroma

Alejandro A. Hidalgo, Roberto Paredes, Victor M. Garcia, Geraldine Flynn, Candace S. Johnson, Donald L. Trump, Sergio A. Onate

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)731-736
Number of pages6
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume103
Issue number3-5
DOIs
Publication statusPublished - Mar 2007

Keywords

  • Coactivator
  • Corepressor
  • Nuclear receptor
  • Prostate cancer microenvironment
  • Prostate cancer stromal cells
  • Transcriptional regulation
  • Vitamin D receptor

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

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