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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. [ABSTRACT FROM AUTHOR]

Cancer cells encounter metabolic stresses such as hypoxia and nutrient limitations because they grow and divide more quickly than their normal counterparts. In response to glucose restriction, we found that nuclear translocation of the glycolic enzyme, pyruvate kinase M2 (PKM2), helped cancer cells survive under the metabolic stress. Restriction of glucose stimulated AMPK activation and resulted in co-translocation of AMPK and PKM2 through Ran-mediated nuclear transport. Nuclear PKM2 subsequently bound to Oct4 and promoted the expression of cancer stemness-related genes, which might enrich the cancer stem cell population under the metabolic stress. Nuclear PKM2 was also capable of promoting cancer metastasis in an orthotopic xenograft model. In summary, we found that cytosolic AMPK helped PKM2 carry out its nonmetabolic functions in the nucleus under glucose restriction and that nuclear PKM2 promoted cancer stemness and metastasis. These findings suggested a potential new targeting pathway for cancer therapy in the future. [ABSTRACT FROM AUTHOR]

Endocan is known to be a circulating dermatan sulfate proteoglycan that regulates endothelial cell function. Dysregulation of endocan expression is observed not only in the tumor vasculature but also in cancer cells. Accumulating evidence has revealed that disordered endocan facilitates cancer progression via enhancing cancer cell proliferation, cell mobility, and cancer stemness properties. Recently, various interacting proteins and diverse subcellular localizations of endocan were identified in cancer cells. Herein, we summarize the application of endocan in cancer diagnoses and prognoses using serum and tumor specimens. We further discuss that the aberrant molecular characteristics of endocan may be due to the mislocalization of endocan in cancer cells. Defining the specific cellular roles of endocan will provide a promising diagnostic factor and therapeutic target for cancer patients. • Critical roles of endocan have been revealed in the regulation of cancer cell behaviors during cancer progression. • Secretory endocan binds and affects signaling of growth factors, receptor tyrosine kinases, and adhesion molecules in a tumor. • Cytosolic endocan correlates with tumor progression while nuclear endocan acts as a transcriptional cofactor to promote cancer stemness. • Subpopulations such as EFGR-mutated NSCLC cells and prostate cancer stem cells were more sensitive to endocan targeting. • Understanding the roles of endocan in cancers can promote the development of diagnostic and therapeutic innovations. [ABSTRACT FROM AUTHOR]