Androgen dihydrotestosterone promotes bladder cancer cell proliferation and invasion via EPPK1-mediated MAPK/JUP signaling

Abstract

Abstract The incidence of bladder cancer (BLCA) in men is higher than that of women. Differences in androgen levels between men and women are considered the main causes of incidence rate differences. In this study, dihydrotestosterone (DHT) could significantly increase cell proliferation and invasion of BLCA cell line. In addition, BLCA formation and metastatic rates were higher in N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) treated male mice than in female and castrated male mice in vivo. However, immunohistochemistry showed that androgen receptor (AR) was found low expressed in normal and BLCA cancer tissues of men and women. Here, a non-AR combination pathway of androgen that promoted BLCA development was investigated. The protein EPPK1 was bombinated with DHT determined by biotinylated DHT-binding pull-down experiments. EPPK1 was highly expressed in BLCA tissues, and EPPK1 knockdown significantly inhibited BLCA cell proliferation and invasion promoted by DHT. Moreover, JUP expression was elevated in DHT-treated high-EPPK1 expression cells, and JUP knockdown inhibited cell proliferation, and invasion. EPPK1 over-expression could increase tumor growth in nude mice and JUP expression. Furthermore, DHT increased the expression of MAPK signals p38, p-p38, and c-Jun expression, and c-Jun could combine with the JUP promoter. However, no functions in EPPK1 knockdown cells and p38 inhibitor could suppress the DHT-treated increase, indicating that p38 MAPK may be involved in the regulation of DHT-dependent EPPK1-JUP-promoting BLCA cell proliferation and invasion. The growth of bladder tumors in BBN-treated wild mice was inhibited by the addition of the hormone inhibitor Goserelin. Our findings indicated the potential oncogenic role and mechanism of DHT in BLCA pathogenesis through a non-AR pathway, which may serve as a novel therapeutic target for BLCA. Androgen inhibitors may be used as endocrine therapy for bladder cancer.