NSUN4-mediated m5C modification of circERI3 promotes lung cancer development by altering mitochondrial energy metabolism

As a highly important methylation modification, the 5-methyladenosine (m5C) modification can profoundly affect RNAs by regulating their transcription, structure and stability. With the continuous development of high- throughput technology, differentially expressed circular RNAs (circRNAs) have been increasingly discovered, and circRNAs play unique roles in tumorigenesis and development. However, the regulatory mechanism of the m5C modification of circRNAs has not yet been revealed. In this study, circERI3, which is highly expressed in lung cancer tissue and significantly correlated with the clinical progression of lung cancer, was initially identified through differential expression profiling of circRNAs. A combined m5C microarray analysis revealed that circERI3 contains the m5C modification and that the NSUN4-mediated m5C modification of circERI3 can increase its nuclear export. The important function of circERI3 in promoting lung cancer progression in vitro and in vivo was clarified. Moreover, we elucidated the novel mechanism by which circERI3 targets DNA binding protein 1 (DDB1), regulates its ubiquitination, enhances its stability, and in turn promotes the transcription of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) through DDB1 to affect mitochondrial function and energy metabolism, which ultimately promotes the development of lung cancer. This study not only revealed the reasons for the abnormal distribution of circERI3 in lung cancer tissues from the perspective of methylation and clarified the important role of circERI3 in lung cancer progression but also described a novel mechanism by which circERI3 promotes lung cancer development through mitochondrial energy metabolism, providing new insights for the study of circRNAs in lung cancer.