circPDE5A regulates prostate cancer metastasis via controlling WTAP-dependent N6-methyladenisine methylation of EIF3C mRNA.

ABSTRACT

BACKGROUND: Circular RNA (circRNA) is a novel class noncoding RNA (ncRNA) that plays a critical role in various cancers, including prostate cancer (PCa). However, the clinical significance, biological function, and molecular mechanisms of circRNAs in prostate cancer remain to be elucidated. METHODS: A circRNA array was performed to identified the differentially expressed circRNAs. circPDE5A was identified as a novel circRNA which downregulated in clinical samples. Functionally, the in vitro and in vivo assays were applied to explore the role of circPDE5A in PCa metastasis. Mechanistically, the interaction between circPDE5A and WTAP was verified using RNA pulldown followed by mass spectrometry, RNA Immunoprecipitation (RIP) assays. m6A methylated RNA immunoprecipitation sequencing (MeRIP-seq) was then used to identified the downstream target of circPDE5A. Chromatin immunoprecipitation assay (ChIP) and dual-luciferase reporter assay were used to identified transcriptional factor which regulated circPDE5A expression. RESULTS: circPDE5A was identified downregulated in PCa tissues compared to adjacent normal tissue and was negatively correlated with gleason score of PCa patients. circPDE5A inhibits PCa cells migration and invasion both in vitro and in vivo. circPDE5A blocks the WTAP-dependent N6-methyladenisine (m6A) methylation of eukaryotic translation initiation factor 3c (EIF3C) mRNA by forming the circPDE5A-WTAP complex, and finally disrupts the translation of EIF3C. Moreover, the circPDE5A-dependent decrease in EIF3C expression inactivates the MAPK pathway and then restrains PCa progression. CONCLUSIONS: Our findings demonstrate that FOXO4-mediated upregulation of circPDE5A controls PCa metastasis via the circPDE5A-WTAP-EIF3C-MAPK signaling pathway and could serve as a potential therapeutic targer for PCa.