Proteomic profiling of zinc-induced skin cell proliferation: Activation of beta-catenin pathway

Background: Zinc is an essential micronutrient that plays important roles in protein structure, catalysis, and gene regulation. It is required for the homeostasis of human skin. However, the effect of zinc on skin cell proliferation and its underlying mechanisms remain elusive. Objective: To investigate the molecular changes underlying zinc-induced cell proliferation and its mechanisms. Methods and results: We investigate cell proliferation, cell migration and cell apoptosis using human keratinocyte HaCaT and the fibroblast WS1 cells treated with or without zinc and found that exposure to zinc for 30 min was sufficient to induce significant cell proliferation. we analyzed protein expression in control and zinc-treated cells via iTRAQ protein profiling which identified 16 upregulated and 64 downregulated proteins between control and zinc-treated HaCaT cells (fold-change > 1.2). Through bioinformatic analysis, common motifs that associated with transcriptional factors or co-activators were identified, including β-catenin, YY1 and E2F1. Among them, the β-catenin signaling pathway was further investigated. Zinc induced the nuclear translocation of β-catenin and increased β-catenin-responsive luciferase activity in skin cells. The growth advantage of zinc was abrogated by siRNA targeting β-catenin or XAV-939 which is an inhibitor of the β-catenin pathway. Moreover, zinc-induced resistance to H2O2 was significantly decreased by XAV-939. Conclusion: Our findings reveal the molecular changes in zinc-induced skin cell proliferation and in which the β-catenin mediates the pro-proliferative role of zinc in skin cells.