Abstract: Background and purpose: Nuclear receptor hepatocyte nuclear factor 4α (HNF4α) is a critical transcriptional factor, however, the functional and regulatory role of HNF4α in prostate cancer is not clear. The aim of this study was to investigate the mechanism of HNF4α involved in the development of castration-resistant prostate cancer. Methods: Oncomine analysis was used to characterize the expression level of HNF4α in clinical samples of prostate cancer. cBioPortal analysis was used to study the alteration of HNF4α in different subtypes of prostate cancer. The overall survival of prostate cancer patients with altered and unaltered HNF4α was also compared. The plenti-HNF4α vector was constructed and transfected into HEK-293 cells for lentivirus package. HNF4α was ectopically expressed in LNCaP cells, and its effect on androgen receptor (AR) expression level was analyzed by real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR) and Western blot. Luciferase reporter assay was performed to study the potential binding effect of HNF4α on AR promoter. Results: HNF4α was upregulated in clinical samples of prostate cancer, and the proportion of abnormal changes in castration-resistant prostate cancer and neuroendocrine prostate cancer samples was significantly increased, which was negatively correlated with the overall survival rate of patients. The exogenous upregulation of HNF4α significantly promoted the expression of AR, and was positively correlated with the expression of the luciferase reporter gene. Conclusion: HNF4α is upregulated in prostate cancer and likely promotes AR expression by directly targeting the AR promoter. HNF4α may serve as a new therapeutic target in prostate cancer.

Key words: Nuclear receptor, Hepatocyte nuclear factor 4α, Prostate cancer, Castration-resistant prostate cancer, Neuroendocrine prostate cancer