Oncogenetic Cul4A Determines The Response To Thalidomide Treatment In Prostate Cancer

We previously showed that Cul4A is overexpressed and amplified in breast cancer, squamous cell carcinomas,adrenocortical carcinomas, childhood medulloblastoma,hepatocellular and malignant pleural mesothelioma. But its role in Pca (Pca) is not known. Thalidomide is a widely used agent against human malignancies including Pca, althouth the mechanisms are not clear. Recent study identified cereblon (CRBN), as a thalidomide primary target. CRBN forms an E3 ubiquitin ligase complex with Cul4A. Thus, we hypothesised thalidomide exerts its anti-tumor effects by suppressing oncogenetic Cul4A in Pca. Here, we show that Cul4A overexpression is frequently detected in PCa tissues and cell lines. High Cul4A levels were associated with Gleason scores and PSA and shorter overall survial. Decreasing Cul4A by shRNA inhibited cell proliferation, anchorage-independent growth, caused cell cycle arrest and induced apoptosis. Notably, Ectopic overexpression of Cul4A in human normal prostate epithelial cell RWPE led to increased migration and invasion and anchorage-independent growth that was attenuated by the ERK inbitibor U0126. Cul4A-shRNA-transfected cells exhibited slower growth of xenograft tumors in nude mice. We observed that the inhibitory effects of thalidomide is positively correlated with Cul4A expression in a wide variety of prostate cells. Overexpression of Cul4A greatly sensitized PC-3 to thalidomide, while, Cul4A suppression significantly reduced the sensitivity of 22RV1 to thalidomide. Mechanistically, Cul4A upregulated phosphorylation of ERK1/2 and TNF-a and thalidomide decreased Cul4A and p-ERK in a time and dose-dependent manner. These results suggest that Cul4A is a potential therapeutic target for Pca and may serve as a biomarker for assessing prognosis of humans with Pca and response to thalidomide treatment.