Loss of ZDHHC-medicated Scribble palmitoylation disrupts cell polarity and promotes prostate cancer progression

Progression and metastasis of prostate cancers (PCs), especially the castration-resistant PC (CRPC) are major therapeutic challenges, with urgent unmet medical needs. However, the underlying mechanisms of the progression of PCs remain unclear. The apical-basal polarity of epithelial cells plays critical roles in regulating normal cell migration and proliferation in prostate. Loss of cell polarity leads to tissue disorganization, uncontrolled proliferation and migration, hallmarks of prostate cancer progression and metastasis. Recently, we discovered that palmitoylation (the C16 fatty acid modification of protein) is critical for the functions of the cell polarity regulator Scribble (SCRIB), and ZDHHC7 is the palmitoyl acyltransferase regulating SCRIB. Interestingly, preliminary analysis of public dataset revealed that ZDHHC7 is frequently deleted in advanced PCs, suggesting that loss of ZDHHC7 might lead to SCRIB mislocalization, disruption of cell polarity, and promoting metastasis of advanced PCs, which has not been studied previously. Furthermore, palmostatin B, a small molecule inhibitor of de-palmitoylation enzymes could enhance SCRIB palmitoylation, and provide potential therapeutic strategies for advanced PCs. We hypothesized that the signal transduction network involving ZDHHC7, SCRIB and the downstream YAP, MAPK or PI3K/AKT pathways contribute to progression of prostate cancers. We will determine the roles of cell polarity regulator Scribble in prostate cancer cell progression, examine how protein palmitoylation mediates Scibble regulation, and test the efficacy of small molecule inhibitors of de-palmitoylating enzymes.