N6-methyladenosine-modified circRPS6KC1 regulated cell senescence in prostate cancer via FOXM1/PCNA axis

Background Prostate cancer (PCa) gradually becomes the most common cancer in men in many countries, of which circRNAs and methylated modification exert an essential role in prostate cancer progression. However, the concrete mechanism of N6-methyladenosine (m6A) modification of circRNAs in prostate cancer remains unclear. Methods circRNA-seq and bioinformatic analysis reveal the novel up-regulated circRPS6KC1 in PCa. Function experiments in vitro and in vivo, such as colony formation assay, cell counting kit-8 assay, cell cycle analysis, EdU assays, senescence associated β-galactosidase staining and subcutaneous xenograft tumor models, were conducted to show the effect of circRPS6KC1 on prostate cancer cell senescence. RNA Immunoprecipitation (RIP), methylated RNA Immunoprecipitation (MeRIP), RNA pull-down, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were performed to explore the regulatory mechanism. Results We identified a novel circRNA, circRPS6KC1, which was significantly up-regulated in prostate cancer cells and clinical tissues. METTL3/YTHDF1 participated in the m6A modification of circRPS6KC1 and stabilized it. Suppression of circRPS6KC1 contributed to cell senescence in prostate cancer. Mechanically, circRPS6KC1 acted as the miR-761 sponge to regulate the FOXM1 expression. FOXM1 mediated the transcription of PCNA and influenced the p21 degradation, which resulted in p21 up-regulation induced in a p53-independent manner. Conclusion N6-methyladenosine modification by METTL3/YTHDF1 stabilized circRPS6KC1, and circRPS6KC1 regulated cell senescence in prostate cancer via FOXM1/PCNA axis in a p53-independent manner.