Alpha‐2‐glycoprotein 1, zinc‐binding (AZGP1), known as zinc‐alpha‐2‐glycoprotein (ZAG), is a multifunctional secretory glycoprotein and relevant to cancer metastasis. Little is known regarding the underlying mechanisms of AZGP1 in prostate cancer (PCa). In the present study, we report that AZGP1 is an androgen‐responsive gene, which is involved in AR‐induced PCa cell proliferation and metastasis. In clinical specimens, the expression of AZGP1 in PCa tissues is markedly higher than that in adjacent normal tissues. In cultures, expression of AZGP1 is upregulated by the androgen‐AR axis at both messenger RNA and protein levels. Furthermore, Chip‐Seq assay identifies canonical androgen‐responsive elements (AREs) at AZGP1 enhancer; and dual‐luciferase reporter assays reveal that the AREs is highly responsive to androgen whereas mutations of the AREs abolish the reporter activity. In addition, AZGP1 promotes G1/S phase transition and cell cycle progress by increasing cyclin D1 levels in PCa cells. Functional studies demonstrate that knocking down endogenous AZGP1 expression in LNCaP and CWR22Rv1 cells largely weaken androgen/AR axis‐induced cell migration and invasion. In vivo xenotransplantation tumor experiments also show that AZGP1 involves in androgen/AR axis‐mediated PCa cell proliferation. Taken together, our study implicates for the first time that AZGP1 is an AR target gene and is involved in androgen/AR axis‐mediated cell proliferation and metastasis in primary PCa.

Phloretin is a flavonoid existed in various plants and has been reported to possess anticarcinogenic activity. However, the anticancer mechanism of phloretin in prostate cancer (PCa) remains unclear. Here, our in vitro and in vivo experimental data demonstrate that phloretin inhibits the phosphorylation and the activation of EGFR and then inhibits its downstream PI3K/AKT and MEK/ERK1/2 pathways in PCa cells. Inhibition of these two pathways further decreases expression of Sp1 by inhibiting Sp1 gene transcription, induces degradation of Sp1 protein by inhibiting GSK3β phosphorylation, suppresses nucleolin-enhanced translation of Sp1 mRNA by inhibiting nucleolin phosphorylation, and directly inactivates transcription activity of Sp1. Inhibition of Sp1 subsequently decreases the expression of Sp3/4, VEGF, and Survivin and then upregulates apoptosis-related proteins and downregulates cell cycle-related proteins in PCa cells. Finally, phloretin treatment in PCa cells induces cell growth inhibition and apoptosis, suggesting that phloretin may be an effective therapy compound in the treatment of prostate cancer.