Direct interaction of β-catenin with nuclear ESM1 supports stemness of metastatic prostate cancer
Journal
EMBO Journal
Journal Volume
40
Journal Issue
4
Date Issued
2021
Author(s)
Abstract
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. ? 2020 The Authors
Subjects
cancer stemness; tumor metastasis; Wnt-β-catenin
SDGs
Other Subjects
beta catenin; endothelial cell specific molecule 1; proteoglycan; transcription factor 4; unclassified drug; Wnt protein; beta catenin; CTNNB1 protein, human; ESM1 protein, human; proteoglycan; tumor marker; tumor protein; animal cell; animal experiment; animal model; armadillo repeat domain; Article; cancer stem cell; canonical Wnt signaling; complex formation; controlled study; correlation analysis; human; human cell; male; metastasis; metastatic prostate cancer; mouse; nonhuman; overall survival; prostate cancer; protein expression; protein protein interaction; protein structure; transactivation; tumor invasion; animal; apoptosis; cell nucleus; cell proliferation; drug screening; gene expression regulation; genetics; lung tumor; metabolism; nonobese diabetic mouse; pathology; prognosis; prostate tumor; SCID mouse; tumor cell culture; Animals; Apoptosis; beta Catenin; Biomarkers, Tumor; Cell Nucleus; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Male; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Proteins; Neoplastic Stem Cells; Prognosis; Prostatic Neoplasms; Proteoglycans; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
Publisher
Wiley-VCH Verlag
Type
journal article