ABSTRACT
BACKGROUND: Prostate cancer (PCa) is a commonly diagnosed malignant cancer and is the second- highest cause of cancer death in men worldwide. Enzalutamide is the second-generation inhibitor of androgen receptor signaling and is the fundamental drug for the treatment of advanced PCa. However, the disease will eventually progress to metastatic castration-resistant prostate cancer (CRPC) and aggressive neuroendocrine prostate cancer (NEPC) because of androgen-deprivation therapy (ADT) resistance. The aim of the study was to investigate the role of long non-coding RNA (lncRNA) AFAP1-AS1 in ADT resistance. METHODS: Quantitative real-time PCR analysis (qPCR) was used to assess the expression of AFAP1-AS1 in PCa cell lines and tissues. Cell proliferation and invasion were assessed after AFAP1-AS1 knockdown using Cell Counting Kit (CCK)-8 and Transwell assay, respectively. A dual-luciferase reporter gene assay was carried out to validate the regulatory relationship among AFAP1-AS1, microRNA (miR)-15b, and insulin-like growth factor1 receptor (IGF1R). RESULTS: AFAP1-AS1 level was markedly increased in castration-resistant C4-2 cells and NE-like cells (PC3, DU145, and NCI-H660), compared with androgen-sensitive LNCaP cells. Enzalutamide treatment increased the expression of AFAP1-AS1 in vitro and in vivo. Functionally, AFAP1-AS1 knockdown repressed tumor cell proliferation and invasion. Mechanistically, AFAP1-AS1 functioned as an oncogene in PCa through binding to miR-15b and destroying its tumor suppressor function. Finally, we identified that AFAP1-AS1 up-regulated IGF1R expression by competitively binding to miR-15b to de-repress IGF1R. CONCLUSION: AFAP1-AS1 facilitates PCa progression by regulating miR-15b/IGF1R axis, indicating that AFAP1-AS1 may serve as a diagnostic biomarker and therapeutic target for PCa.
Subject(s)
MicroRNAs , Prostatic Neoplasms , RNA, Long Noncoding/genetics , Receptor, IGF Type 1 , Androgen Antagonists , Cell Line, Tumor , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic , Humans , Male , MicroRNAs/genetics , MicroRNAs/metabolism , Oncogenes , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/genetics , RNA, Long Noncoding/metabolism , Receptor, IGF Type 1/genetics , Receptor, IGF Type 1/metabolismABSTRACT
Prostate cancer (PCa) is one of the leading causes of cancer-related death worldwide, and it is almost incurable once it has developed into castration-resistance prostate cancer (CRPC). However, the mechanisms underlying the oncogenesis of PCa and CRPC remain elusive. Lysine-specific histone demethylase 5C (KDM5C) is an important member of lysine demethylase family and has recently been found highly expressed in multiple cancer types. In this study, we reported that KDM5C was highly expressed in PCa and CRPC specimens, and the high expression promoted CRPC cell proliferation through repressing phosphatase and tensin homolog (PTEN) gene epigenetically. Moreover, KDM5C was transcriptionally upregulated by bromodomain-containing protein 4 (BRD4), and knockdown KDM5C sensitized the therapeutic effects of CRPC cells to the bromodomain and extraterminal (BET) inhibitor. Taken together, our study uncovers that the BRD4-KDM5C-PTEN may be a new oncogenic pathway in CRPC development, and KDM5C is a critical protein and could be an ideal target for CRPC treatment in this oncogenic pathway.
