Direct interaction of β‐catenin with nuclear ESM1 supports stemness of metastatic prostate cancer

• Published in: The EMBO journal Vol. 40; no. 4; pp. e105450 - n/a
• Main Authors: Pan, Ke‐Fan, Lee, Wei‐Jiunn, Chou, Chun‐Chi, Yang, Yi‐Chieh, Chang, Yu‐Chan, Chien, Ming‐Hsien, Hsiao, Michael, Hua, Kuo‐Tai
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.02.2021; Blackwell Publishing Ltd; John Wiley and Sons Inc
• Subjects: Animals; Apoptosis; beta Catenin - genetics; beta Catenin - metabolism; Biomarkers; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; cancer stemness; Catenin; Cell Nucleus - metabolism; Cell Proliferation; Cell self-renewal; Diagnostic systems; EMBO03; EMBO34; EMBO37; Endothelial cells; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Male; Metastases; Metastasis; Mice; Mice, Inbred NOD; Mice, SCID; Mutation; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Prognosis; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proteoglycans; Proteoglycans - genetics; Proteoglycans - metabolism; Signal transduction; Signaling; Stem cells; Therapeutic targets; Tumor Cells, Cultured; tumor metastasis; Wnt protein; Wnt‐β‐catenin; Xenograft Model Antitumor Assays; Wnt‐β‐catenin; cancer stemness; tumor metastasis; Wnt-β-catenin
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.15252/embj.2020105450

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. SYNOPSIS Aberrant activation of the Wnt/β‐catenin pathway can promote stem cell self‐renewal and expansion in cancer. Here, mislocalized secretory proteoglycan ESM1 is implicated in the nuclear coordination of Wnt/β‐catenin signaling, thus supporting prostate cancer (PCa) stemness and metastasis. Nuclear ESM1 regulates PCa metastasis by promoting cancer stem cell properties. ESM1 associates with β‐catenin to stabilize the β‐catenin/TCF4 complex and promote Wnt activation. A positive feed‐forward loop between activated β‐catenin and nuclear ESM1 maintains Wnt‐mediated PCa stemness. Graphical Abstract Mislocalised secretory proteoglycan ESM1 stabilizes β‐catenin/TCF4 complexes to enhance Wnt activation in cancer stem cells.