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

Abstract

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.

An 11-GRG Predicting Model for UCEC Prognosis

“…Among the 11 GRGs examined, GPI is a predictor of outcomes in UCEC patients [36][37][38] as well as other cancers [39][40][41][42] . Similarly, other genes such as HK1 43,44 , PDHA1 [45][46][47] , PGK2 48 , NUP155 49 , PC [50][51][52] , ALDOB [53][54][55][56] , and PFKM 57,58 have been implicated in carcinogenesis and have demonstrated effects on patient prognoses in various cancer types. We observed that PDHA1 and GPI exhibit the highest positive correlation.…”

Role of N6‑methyladenosine in the pathogenesis, diagnosis and treatment of prostate cancer (Review)

“…The methyltransferase complex is composed of WTAP/METTL3/METTL14, which increases circDDIT4 levels, while FTO exerts the opposite effect ( 125 ). The circRBM33-FMR1 complex stabilizes PDHA1 mRNA in an m 6 A-dependent manner and activates the mitochondrial metabolism of PCa, thereby promoting PCa progression ( 126 ).…”

Copper homeostasis and cuproptosis in cancer immunity and therapy

“…PDHA1 is negatively regulated by activating protein 2 alpha (AP2α) in cervical cancer cells to control aggressive characteristics and aerobic glycolysis 98 . CircRBM33 modified by N 6 ‐methyladenosine (m 6 A) contributes to prostate carcinoma progression through PDHA1‐mediated mitochondrial respiration modulation as well as attenuates the response to androgen receptor signaling inhibitor treatment 99 …”

“…98 CircRBM33 modified by N 6 -methyladenosine (m 6 A) contributes to prostate carcinoma progression through PDHA1-mediated mitochondrial respiration modulation as well as attenuates the response to androgen receptor signaling inhibitor treatment. 99 SIRT3 is a major mitochondrial acetyl-lysine deacetylase and a tumor suppressor in the mitochondria, which deacetylates PDHA1 lysine 321 as well as increases its activity in cancer cells. 100 PGC1α, a central mediator of mitochondrial metabolism, upregulates PDHA1 and MPC1 for reversing the Warburg effects to elevate pyruvate flux into the mitochondria for oxidation, and to promote mitochondrial biogenesis and fusion to control the metabolic transformation to oxidative phosphorylation, thus promoting cholangiocarcinoma metastases.…”