Ligand-dependent inhibition of β-catenin/TCF signaling by androgen receptor

Dennis R. Chesire, William B Isaacs

Research output: Contribution to journalArticle

Abstract

β-catenin signaling may contribute to prostate cancer (CaP) progression. Although β-catenin is known to upregulate T cell factor (TCF) target gene expression in CaP cells, recent evidence demonstrates its capacity to enhance ligand-dependent androgen receptor (AR) function. Thus, we wished to further understand the interaction between these two pathways. We find in both CaP cells (CWR22-Rv1, LAPC-4, DU145) and non-CaP cells (HEK-293, TSU, SW480, HCT-116) that β-catenin/TCF-related transcription (CRT), as measured by activation of a synthetic promoter and that of cyclin D1, is inhibited by androgen treatment. This inhibition is AR-dependent, as it only occurs in cells expressing AR endogenously or transiently, and is abrogated by AR antagonists. Additional analyses convey that the ligand-dependent nature of CRT suppression depends on transactivation-competent AR in the nucleus, but not on indirect effects stemming from AR target gene expression. Given the recent work identifying an AR/β-catenin interaction, and from our finding that liganded AR does not prompt gross changes in the constitutive nuclear localization of TCF4 or mutant β-catenin, we hypothesized that transcription factor (i.e. AR and TCF) competition for β-catenin recruitment may explain, in part, androgen-induced suppression of CRT. To address this idea, we expressed an AR mutant lacking its DNA-binding domain (DBD). This receptor could not orchestrate ligand-dependent CRT repression, thereby providing support for those recent data implicating the AR DBD/LBD as necessary for β-catenin interaction. Further supporting this hypothesis, TCF/LEF over-expression counteracts androgen-induced suppression of CRT, and requires β-catenin binding activity to do so. Interestingly, TCF4 over-expression potently antagonizes AR function; however, this inhibition may occur independently of β-catenin/TCF4 interaction. These results from TCF4 over-expression analyses, taken together, provide further evidence that AR-mediated suppression of CRT is a consequence of limiting amounts of β-catenin, and not AR target gene expression. Our analyses point to a reciprocal balance between AR and CRT function that may shape critical processes during normal prostate development and tumor progression.

Original languageEnglish (US)
Pages (from-to)8453-8469
Number of pages17
JournalOncogene
Volume21
Issue number55
DOIs
StatePublished - Dec 5 2002

Fingerprint

TCF Transcription Factors
Catenins
Androgen Receptors
Ligands
Androgens
Gene Expression
Androgen Receptor Antagonists
HEK293 Cells
DNA
Cyclin D1

Keywords

  • β-catenin
  • Androgen receptor
  • Nuclear signaling
  • Prostate
  • TCF/LEF

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Ligand-dependent inhibition of β-catenin/TCF signaling by androgen receptor. / Chesire, Dennis R.; Isaacs, William B.

In: Oncogene, Vol. 21, No. 55, 05.12.2002, p. 8453-8469.

Research output: Contribution to journalArticle

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