Androgen receptor level controlled by a suppressor complex lost in an androgen-independent prostate cancer cell line

Oncogene. 2004 Jul 1;23(30):5175-84. doi: 10.1038/sj.onc.1207654.

Abstract

Androgen receptor (AR) overexpression is one of the characteristics of prostate cancer (PC) that progresses to hormone independence. An androgen-independent (AI) derivative, with much higher AR-mRNA and protein levels than the parental LNCaP cell line, whose proliferation was androgen dependent (AD), was used to explore the mechanism of AR overexpression. We found that a suppressor element (ARS), previously identified in mouse AR and located in the 5'-untranslated region of human AR gene, malfunctions in AI cells. Transfection of constructs that included ARS element into AD cells reduced the transactivating activities of both AR promoter and a heterologous SV40 promoter. The deletion of ARS resulted in an eightfold increase in AR-promoter activity in AD cells, but had no effect in AI cells. Moreover, the nuclear extracts of AD cells contained proteins that produced a specific, ARS-binding complex, while this complex appeared to have been lost from AI cells. Most importantly, treatment of AI cells with a demethylating agent or histone deacetylase inhibitors restored the lost ARS-binding complex. The restoration of the complex coincided with a reduced expression of AR-mRNA and protein and a reduced rate of AR-gene transcription, determined by nuclear run-on experiment. Thus, epigenetic transcriptional silencing of the suppressor protein(s) may be responsible for AR overexpression in AI cells, and its reversal in hormone-independent PC may normalize AR levels and restore their hormone dependence.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 5' Untranslated Regions
  • Carcinoma / metabolism
  • Cell Division
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Enzyme Inhibitors / pharmacology
  • Gene Deletion
  • Gene Expression Regulation, Neoplastic*
  • Gene Silencing
  • Genes, Reporter
  • Genes, Tumor Suppressor*
  • Humans
  • Hydroxamic Acids / pharmacology
  • Luciferases / metabolism
  • Male
  • Promoter Regions, Genetic
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Proteins / analysis
  • RNA, Messenger / analysis
  • Receptors, Androgen / drug effects
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Transcription, Genetic / drug effects
  • Transcriptional Activation
  • Transfection

Substances

  • 5' Untranslated Regions
  • Enzyme Inhibitors
  • Hydroxamic Acids
  • Proteins
  • RNA, Messenger
  • Receptors, Androgen
  • trichostatin A
  • Luciferases