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

Abstract

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.

Coordinated Action of Hypoxia-inducible Factor-1α and β-Catenin in Androgen Receptor Signaling

“…Thus, hypoxia inhibits ␤-catenin-mediated TCF signaling. In addition, AR inhibits TCF activity in a ligand-dependent manner (35). These results indicate that, rather than activating the transcriptional activity of TCF in hypoxia, ␤-catenin together with HIF-1␣ enhance the transcriptional activity of AR under low androgen environmental conditions and that HIF-1␣ enhances the function of ␤-catenin in AR transactivation.…”

Stromally Expressed c-Jun Regulates Proliferation of Prostate Epithelial Cells

“…To examine whether stromal expression of c-Jun is specific to nontumorigenic cells, we used the androgendependent CWR22-Rv1 prostate cancer cells 45,46 in our monoculture and co-culture experiments. CWR22-Rv1 prostate cancer cells had increased proliferation rate when co-cultured with c-jun ϩ/ϩ fibroblasts (see Supplemental Figure S1A, available online at http://ajp.amjpathol.…”

Wnt3a Growth Factor Induces Androgen Receptor-Mediated Transcription and Enhances Cell Growth in Human Prostate Cancer Cells

“…2F). It has been shown that overexpression of TCF/LEF and E-cadherin can compete for ␤-catenin binding to AR and reduce AR-mediated transactivation (31,32). We therefore tested whether coexpression of TCF-1 and E-cadherin can affect the induction of AR activity mediated by Wnt3a-CM.…”