CircRHBDD1 augments metabolic rewiring and restricts immunotherapy efficacy via m6A modification in hepatocellular carcinoma
Juan Cai, Zhiqiang Chen, Yao Zhang, Jinguo Wang, Zhengrong Zhang, Jindao Wu, Jiading Mao, Xueliang Zuo
Abstract
Circular RNAs are a class of highly conserved RNAs with stable covalently closed circular structures. Metabolic reprogramming of cancer cells reshapes the tumor microenvironment and can suppress antitumor immunity. Here, we discovered a novel circular RNA, termed circRHBDD1, which augments aerobic glycolysis and restricts anti-PD-1 therapy in hepatocellular carcinoma (HCC). Mechanistic studies revealed that circRHBDD1 recruits the m6A reader YTHDF1 to PIK3R1 mRNA and accelerates the translation of PIK3R1 in an m6A-dependent manner. EIF4A3-mediated exon back-splicing contributes to the upregulation of circRHBDD1. Moreover, circRHBDD1 is highly expressed in anti-PD-1 responder HCC patients, and targeting circRHBDD1 improves anti-PD-1 therapy in an immune-competent mouse model. Overall, these findings illustrate the metabolic importance of the circRHBDD1/YTHDF1/PIK3R1 axis in HCC and show that suppression of circRHBDD1 may bolster the efficacy of anti-PD-1 therapy for HCC treatment. Circular RNAs are a class of highly conserved RNAs with stable covalently closed circular structures. Metabolic reprogramming of cancer cells reshapes the tumor microenvironment and can suppress antitumor immunity. Here, we discovered a novel circular RNA, termed circRHBDD1, which augments aerobic glycolysis and restricts anti-PD-1 therapy in hepatocellular carcinoma (HCC). Mechanistic studies revealed that circRHBDD1 recruits the m6A reader YTHDF1 to PIK3R1 mRNA and accelerates the translation of PIK3R1 in an m6A-dependent manner. EIF4A3-mediated exon back-splicing contributes to the upregulation of circRHBDD1. Moreover, circRHBDD1 is highly expressed in anti-PD-1 responder HCC patients, and targeting circRHBDD1 improves anti-PD-1 therapy in an immune-competent mouse model. Overall, these findings illustrate the metabolic importance of the circRHBDD1/YTHDF1/PIK3R1 axis in HCC and show that suppression of circRHBDD1 may bolster the efficacy of anti-PD-1 therapy for HCC treatment.