Benign prostatic hyperplasia (BPH) is a common disease in elderly men with an uncertain etiology and mechanistic basis. Metabolic syndrome (MetS) is also a very common illness and is closely related to BPH. Simvastatin (SV) is one of the widely used statins for MetS. Peroxisome-proliferator-activated receptor gamma (PPARγ), crosstalking with the WNT/β-catenin pathway, plays important roles in MetS. Our current study aimed to examine SV-PPARγ-WNT/β-catenin signaling in the development of BPH. Human prostate tissues and cell lines plus a BPH rat model were utilized. Immunohistochemical, immunofluorescence, hematoxylin and eosin (H&E) and Masson’s trichrome staining, construction of a tissue microarray (TMA), ELISA, CCK-8 assay, qRT-PCR, flow cytometry, and Western blotting were also performed. PPARγ was expressed in both prostate stroma and epithelial compartments and downregulated in BPH tissues. Furthermore, SV dose-dependently triggered cell apoptosis and cell cycle arrest at the G0/G1 phase and attenuated tissue fibrosis and the epithelial–mesenchymal transition (EMT) process both in vitro and in vivo. SV also upregulated the PPARγ pathway, whose antagonist could reverse SV produced in the aforementioned biological process. Additionally, crosstalk between PPARγ and WNT/β-catenin signaling was demonstrated. Finally, correlation analysis with our TMA containing 104 BPH specimens showed that PPARγ was negatively related with prostate volume (PV) and free prostate-specific antigen (fPSA) and positively correlated with maximum urinary flow rate (Qmax). WNT-1 and β-catenin were positively related with International Prostate Symptom Score (IPSS) and nocturia, respectively. Our novel data demonstrate that SV could modulate cell proliferation, apoptosis, tissue fibrosis, and the EMT process in the prostate through crosstalk between PPARγ and WNT/β-catenin pathways.

Benign prostatic hyperplasia (BPH) is a common disease in elderly men with uncertain molecular mechanism, and oxidative stress (OS) has also been found associated with BPH development. Recently, we found that prostate‐associated gene 4 (PAGE4) was one of the most significantly changed differentially expressed genes (DEGs) in BPH, which can protect cells against stress stimulation. However, the exact role of PAGE4 in BPH remains unclear. This study is aimed at exploring the effect of PAGE4 in BPH under OS. Human prostate tissues and cultured WPMY‐1 and PrPF cells were utilized. The expression and localization of PAGE4 were determined with qRT‐PCR, Western blotting, and immunofluorescence staining. OS cell models induced with H₂O₂ were treated with PAGE4 silencing or PAGE4 overexpression or inhibitor (N‐acetyl‐L‐cysteine (NAC)) of OS. The proliferation activity, apoptosis, OS markers, and MAPK signaling pathways were detected by CCK‐8 assay, flow cytometry analysis, and Western blotting. PAGE4 was shown to be upregulated in human hyperplastic prostate and mainly located in the stroma. Acute OS induced with H₂O₂ increased PAGE4 expression (which was prevented by OS inhibitor), apoptosis, cell cycle arrest, and reactive oxygen species (ROS) accumulation in WPMY‐1 and PrPF cells. siPAGE4 plus H₂O₂ potentiated H₂O₂ effect via reducing the p‐ERK1/2 level and increasing p‐JNK1/2 level. Consistently, overexpression of PAGE4 offset the effect of H₂O₂ and partially reversed the PAGE4 silencing effect. However, knocking down and overexpression of PAGE4 alone determined no significant effects. Our novel data demonstrated that augmented PAGE4 promotes cell survival by activating p‐ERK1/2 and decreases cell apoptosis by inhibiting p‐JNK1/2 under the OS, which could contribute to the development of BPH.