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

Abstract

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 PCa progression. However, the concrete mechanisms of N6-methyladenosine (m6A) modification of circRNAs in PCa remain unclear. In our study, we identified circRPS6KC1, a novel and up-regulated circular RNA in PCa, through circRNA sequencing. We discovered that METTL3 and YTHDF1 were involved in the m6A modification of circRPS6KC1 and the stabilization. Furthermore, we found that suppression of circRPS6KC1 contributed to cellular senescence in prostate cancer. 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 up-regulation of p21 protein in a p53-independent manner. In conclusion, our findings showed that N6-methyladenosine modification by METTL3 and YTHDF1 stabilized circRPS6KC1, and circRPS6KC1 played an essential role on cellular senescence via FOXM1/PCNA axis in prostate cancer.