Altered corepressor SMRT expression and recruitment to target genes as a mechanism that change the response to androgens in prostate cancer progression

Alejandro S. Godoy, Paula C. Sotomayor, Marcelo Villagran, Rami Yacoub, Viviana P. Montecinos, Eileen M. McNerney, Michael Moser, Barbara A. Foster, Sergio A. Onate

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

Androgen receptor (AR) is required for the development and progression of prostate cancer (CaP) from androgen-dependence to androgen-resistance. Both corepressors and coactivators regulate AR-mediated transcriptional activity, and aberrant expression or activity due to mutation(s) contributes to changes in AR function in the progression to androgen resistance acquired during hormonal ablation therapies. Primary culture of epithelial cells from androgen-dependent CWR22 and androgen-resistant CWR22. R xenograft tumors were used to evaluate the effect of androgens on AR function, and the association with coactivators (SRC-1 and TIF-2) and corepressors (SMRT and NCoR). Both androgen-dependent CWR22 and androgen-resistant CWR22. R cells expressed functional AR as the receptor bind ligand with high affinity and increased trafficking to the nuclei in the presence of androgens. However, in the presence of androgens, AR-mediated transcriptional activity in androgen-sensitive CWR22 cells was limited to a 2-fold increase, as compared to a 6-fold increase in androgen-resistance CWR22. R cells. In androgen-sensitive CWR22 cells, immunoblot, confocal microscopy, and chromatin immunoprecipitation assays indicated that the androgen bound AR transcriptional initiation complex in the PSA promoter contained corepressor SMRT, resulting in limited receptor transcriptional activity. In contrast, increased AR-mediated transcriptional activity in the CWR22. R cells was consistent with decreased expression and recruitment of the corepressors SMRT/NCoR, as well as increased recruitment of the coactivator TIF-2 to the receptor complex. Similar changes in the response to androgens were observed in the LNCaP/C4-2 model of androgen resistance prostate cancer. Thus, altered recruitment and loss of corepressors SMRT/NCoR may provide a mechanism that changes the response of AR function to ligands and contributes to the progression of the advanced stages of human prostate cancer.

Original languageEnglish
Pages (from-to)564-570
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume423
Issue number3
DOIs
Publication statusPublished - 6 Jul 2012

Keywords

  • Androgen receptor
  • CWR22 xenograft
  • Coactivator
  • Corepressor
  • Prostate Cancer
  • Transcription regulation

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Altered corepressor SMRT expression and recruitment to target genes as a mechanism that change the response to androgens in prostate cancer progression'. Together they form a unique fingerprint.

Cite this