Wnt/β‐catenin signaling is frequently activated in advanced prostate cancer and contributes to therapy resistance and metastasis. However, activating mutations in the Wnt/β‐catenin pathway are not common in prostate cancer, suggesting alternative regulations may exist. Here, we report that the expression of endothelial cell‐specific molecule 1 (ESM1), a secretory proteoglycan, is positively associated with prostate cancer stemness and progression by promoting Wnt/β‐catenin signaling. Elevated ESM1 expression correlates with poor overall survival and metastasis. Accumulation of nuclear ESM1, instead of cytosolic or secretory ESM1, supports prostate cancer stemness by interacting with the ARM domain of β‐catenin to stabilize β‐catenin–TCF4 complex and facilitate the transactivation of Wnt/β‐catenin signaling targets. Accordingly, activated β‐catenin in turn mediates the nuclear entry of ESM1. Our results establish the significance of mislocalized ESM1 in driving metastasis in prostate cancer by coordinating the Wnt/β‐catenin pathway, with implications for its potential use as a diagnostic or prognostic biomarker and as a candidate therapeutic target in prostate cancer.

中文翻译：

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β-catenin 与核 ESM1 的直接相互作用支持转移性前列腺癌的干性

Wnt/β-连环蛋白信号在晚期前列腺癌中经常被激活，并导致治疗抵抗和转移。然而，Wnt/β-catenin 通路的激活突变在前列腺癌中并不常见，这表明可能存在替代调节。在这里，我们报告了内皮细胞特异性分子 1 (ESM1) 的表达，一种分泌性蛋白聚糖，通过促进 Wnt/β-catenin 信号传导与前列腺癌干性和进展呈正相关。升高的 ESM1 表达与较差的总生存期和转移相关。核 ESM1 的积累，而不是细胞溶质或分泌 ESM1，通过与 β-catenin 的 ARM 结构域相互作用以稳定 β-catenin-TCF4 复合物并促进 Wnt/β-catenin 信号靶标的反式激活，从而支持前列腺癌干性。因此，激活的 β-catenin 反过来介导 ESM1 的核进入。我们的结果通过协调 Wnt/β-catenin 通路确定了错误定位的 ESM1 在驱动前列腺癌转移中的重要性，这对其作为诊断或预后生物标志物以及作为前列腺癌候选治疗靶点的潜在用途具有重要意义。