Snail1 Negatively Regulates Prostate Cancer Cell Growth, and Drives Prostate Cancer Cell Invasion and Migration in the Context of Tumor Microenvironment

Abstract

Most prostate cancer (PCa) deaths are attributed to cancer metastasis. Despite the high efficacy of anti androgen-receptor signaling therapy in early disease, most PCa patients will develop resistance to the treatment. Roughly 36,000 PCa deaths will be recorded for the year 2025. This represents a large unmet need and calls for a deeper understanding of PCa metastasis. In this report, I investigate the role of Epithelial-Mesenchymal-Transition (EMT) in promoting PCa metastatic potentials. Our understanding of EMT in PCa is growing thanks to the contribution of many investigators. Going forward, my research adheres to the following criteria, to better capture clinical relevance. Partial-EMT should be represented in PCa models. Manipulation of EMT should be transient. Expression of EMT drivers should be at physiological levels. Meeting the described criteria, I’ve discovered that Snail1 (an EMT driver) promotes cancer dormancy through cell proliferation suppression. My work shows Snail1 regulation of EGR1, FOXO1, p21, and cyclins A2 and B2. Snail1-dependent FOXO1 upregulation requires EGR1. Although FOXO1 has been shown to regulate p21, my data strongly suggests that the Snail1/EGR1/FOXO1 axis does not impact Snail1’s ability to regulate p21, cyclin A2 or B2. Furthermore, Snail1 promotion of PCa invasion/migration is dependent on the tumor micro-environment (TME). Snail1’s upregulation of MMP7 and Integrin-β3 is further enhanced by the TME. Herein, I discovered GPR1 as a novel target of Snail1. GPR1 is a G-protein coupled receptor, involved in metastatic progression of breast and gastric cancer. Chemerin, secreted by stromal myofibroblast, is GPR1’s primary ligand. Thus Snail1-dependent upregulation of GPR1, MMP7 and Integrin-β3 suggest the coupling of EMT and the TME to drive PCa metastatic progression. Taken together, Snail1 and its associated circuits serve as viable therapeutic targets for metastatic PCa, having demonstrated that Snail1 can drive both dormancy and invasion/migration.