RNA sequencing of FZD6 knockdown in prostate cancer cells

Wnt signaling is a complex pathway consisting of numerous ligands and frizzled (FZD) receptors. These signaling components are widely expressed in human prostate tissues and often undergo upregulation or mutation in advanced prostate cancers. Enhanced Wnt signaling promotes prostate cancer cell proliferation, metastasis, and resistance to therapy. However, targeting pan-Wnt signaling poses challenges due to tissue toxicity. We show that FZD6 is the most highly expressed and frequently amplified Wnt receptor in advanced human prostate cancers. Knockdown of FZD6 suppresses in vitro growth of various prostate cancer cell lines. Additionally, FZD6 knockdown impairs DNA double-strand break (DSB) repair, as determined by both resolution of γH2AX foci and DNA DSB repair reporter assays. Mechanistically, FZD6 knockdown-induced growth suppression is linked to reduced activities of the SRC kinase and STAT3, while DNA damage repair deficiency is mediated through WEE1 downregulation. WEE1 downregulation is mediated through PLK1 but is independent of β-Catenin. Knockdown of FZD6 enhances the therapeutic efficacy of genotoxic agents in preclinical prostate cancer models. Our findings demonstrate that targeting a single FZD receptor highly expressed in prostate cancers can achieve significant therapeutic efficacy.