Epsins have an important role in mediating clathrin-mediated endocytosis of ubiquitinated cell surface receptors. The potential role for epsins in tumorigenesis and cancer metastasis by regulating intracellular signaling pathways has largely not been explored. Epsins are reportedly upregulated in several types of cancer including human skin, lung, and canine mammary cancers. However, whether their expression is elevated in prostate cancer is unknown. In this study, we investigated the potential role of epsins in prostate tumorigenesis using the wild type or epsin-deficient human prostate cancer cells, LNCaP, in a human xenograft model, and the spontaneous TRAMP mouse model in wild type or epsin-deficient background. Here, we reported that the expression of epsins 1 and 2 is upregulated in both human and mouse prostate cancer cells and cancerous tissues. Consistent with upregulation of epsins in prostate tumors, we discovered that depletion of epsins impaired tumor growth in both the human LNCaP xenograft and the TRAMP mouse prostate. Furthermore, epsin depletion significantly prolonged survival in the TRAMP mouse model. In summary, our findings suggest that epsins may act as oncogenic proteins to promote prostate tumorigenesis and that depletion or inhibition of epsins may provide a novel therapeutic target for future prostate cancer therapies. 1. Introduction Solid tumors, such as those in prostate cancer, contribute the majority of all cancers and result in significant distant tumor metastasis to vital organs such as the lungs, brain, and bones [1, 2]. Prostate cancer contributes significantly to the morbidity and mortality of men in the United States [3]. Advanced prostate cancer is associated with significant mortality because the cancer metastasizes and spreads throughout the body, making recovery nearly impossible [1, 4]. The high rates of prostate cancer metastasis are, in part, caused by aggressive primary tumor growth in prostate [5]. Prostate tumorigenesis is a result of several upregulated signaling pathways, including Notch, EGF, FGF, and Wnt signaling, which promote tumor cell proliferation [6–11]. Understanding the mechanisms responsible for upregulated signaling during early tumorigenesis is an important step in identifying key regulators and potential therapeutic targets. More importantly, targeting early stages of tumorigenesis will facilitate stabilization of rapid growing tumors, leading to effective surgical removal of primary tumors and inhibition of further tumor metastasis. Epsins are endocytic adaptor proteins that regulate
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