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Modulation of the canonical Wnt activity by androgen signaling in prostate epithelial basal stem cells

ABSTRACT: Summary Both the canonical Wnt and androgen receptor (AR) signaling pathways are important for prostate organogenesis and homeostasis. How they crosstalk to regulate prostate stem cell behaviors remains unclear. Here, we show in lineage-tracing mouse models that although Wnt is essential for basal stem cell multipotency, ectopic Wnt activity promotes basal cell over-proliferation and squamous phenotypes, which are counteracted by elevated levels of androgen. In prostate basal cell organoids, dihydrotestosterone (DHT) antagonizes R-spondin-stimulated growth in a concentration-dependent manner. DHT down-regulates the expressions of a Wnt reporter and target genes, and RNA sequencing (RNA-seq) analyses identify Wnt signaling as a key altered pathway. Mechanistically, DHT enhances AR and β-catenin protein binding, and CUT&RUN analyses reveal that ectopic AR sequesters β-catenin away from its Wnt-related cistrome. Our results suggest that an intermediate level of Wnt activity in prostate basal stem cells, achieved via AR-β-catenin interaction, is essential for normal prostate homeostasis. Highlights • Wnt activity is essential for prostate basal cell multipotency but not cancer initiation• Ectopic Wnt activity in prostate basal cells promotes squamous tumor phenotype• Androgen antagonizes Wnt-mediated basal stem cell activity in vivo and in organoids• AR sequesters β-catenin to keep Wnt activities at intermediate levels How Wnt and androgen signaling crosstalk regulates prostate stem cells is unclear. Here, Wang and colleagues show that AR antagonizes Wnt activities within prostate basal cells through sequestering β-catenin, thereby maintaining an intermediate level of Wnt activities essential for basal stem cell multipotency. These findings are important for understanding prostate development and cancer.

SUBMITTER: Horton C

PROVIDER: S-EPMC10277819 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Modulation of the canonical Wnt activity by androgen signaling in prostate epithelial basal stem cells

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