Ligand-dependent inhibition of beta-catenin/TCF signaling by androgen receptor.
Beta-catenin signaling may contribute to prostate cancer (CaP) progression. Although beta-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 beta-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/beta-catenin interaction, and from our finding that liganded AR does not prompt gross changes in the constitutive nuclear localization of TCF4 or mutant beta-catenin, we hypothesized that transcription factor (i.e. AR and TCF) competition for beta-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 beta-catenin interaction. Further supporting this hypothesis, TCF/LEF over-expression counteracts androgen-induced suppression of CRT, and requires beta-catenin binding activity to do so. Interestingly, TCF4 over-expression potently antagonizes AR function; however, this inhibition may occur independently of beta-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 beta-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.
Chesire
Dennis R
DR
Brady Urological Institute Research Laboratories, The Johns Hopkins Medical Institutions, Baltimore, Maryland, MD 21287, USA.
Isaacs
William B
WB
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D008024:Ligands; D008297:Male; D011471:Prostatic Neoplasms; D011944:Receptors, Androgen / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000502:physiology*; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D008024:Ligands; D011944:Receptors, Androgen; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin