Mutual Regulation between Raf/MEK/ERK Signaling and Y-Box―Binding Protein-1 Promotes Prostate Cancer Progression

Y-box-binding protein-1 (YB-1) is known to conduct various functions related to cell proliferation, anti-apoptosis, epithelial-mesenchymal transition, and castration resistance in prostate cancer. However, it is still unknown how YB-1 affects cancer biology, especially its correlations with the mitogen-activated protein kinase (MAPK) signaling pathway. Therefore, we aimed to examine the interaction between YB-1 and the MAPK pathway in prostate cancer. Quantitative real-time PCR, Western blotting, and co-immunoprecipitation assay were conducted in prostate cancer cells. YB-1, phosphorylated YB-1 (p-YB-1), and ERK2 protein expressions in 165 clinical specimens of prostate cancer were investigated by immunohistochemistry. YB-1, p-YB-1, and ERK2 nuclear expressions were compared with clinicopathologic characteristics and patient prognoses. EGF upregulated p-YB-1, whereas MEK inhibitor (U0126, PD98059) decreased p-YB-1. Inversely, silencing of YB-1 using siRNA decreased the expression of ERK2 and phosphorylated MEK, ERK1/2, and RSK. Furthermore, YB-1 interacted with ERK2 and Raf-1 and regulated their expressions, through the proteasomal pathway. Immunohistochemical staining showed a significant correlation among the nuclear expressions of YB-1, p-YB-1, and ERK2. The Cox proportional hazards model revealed that high ERK2 expression was an independent prognostic factor [HR, 7.947; 95% confidence interval (CI), 3.527-20.508; P