M6A-modified circRBM33 promotes prostate cancer progression via PDHA1-mediated mitochondrial respiration regulation and presents a potential target for ARSI therapy

N6-Methyladenosine (m6A) is the most prevalent RNA modification in various types of RNA, including circular RNAs (circRNAs). Mounting evidence has shown that circRNAs may play critical roles in diverse malignancies. However, the biological relevance of m6A modification of circRNAs in prostate cancer (PCa) remains unclear and needs to be elucidated. Our data showed that circRBM33 was m6A-modified and was more highly expressed in PCa cells than in normal cells/tissues. The in vitro and in vivo experiments showed that downregulation/upregulation of circRBM33 inhibited/promoted tumour growth and invasion, respectively. Decreasing m6A levels rescued the tumour-promoting effect of circRBM33. Additionally, once modified by m6A, circRBM33 interacts with FMR1 by forming a binary complex that sustains the mRNA stability of PDHA1, a downstream target gene. Suppressed/overexpressed circRBM33 lowered/enhanced the ATP production, the acetyl-CoA levels and the NADH/NAD+ ratio. Moreover, depletion of circRBM33 significantly increased the response sensitivity to androgen receptor signalling inhibitor (ARSI) therapy, including enzalutamide and darolutamide, in prostate tumours. Our study suggested that the m6A-mediated circRBM33-FMR1 complex can activate mitochondrial metabolism by stabilizing PDHA1 mRNA, which promotes PCa progression, and can attenuate circRBM33 increased ARSI effectiveness in PCa treatment. This newly discovered circRNA may serve as a potential therapeutic target for PCa.