Characterization of RNA editing gene APOBEC3C as a candidate tumor suppressor in prostate cancer

The human genome encodes 19 adenosine and cytidine deaminase genes, classified as A-to-I versus C-to-U editors. A-to-I editors have been widely identified as a promising therapeutic target in various cancers. Conversely, the investigation into C-to-U editors is relatively limited. This study evaluated RNA-editing genes in prostate cancer (PCa). Notably, the APOBEC3 genes are clustered in terms of their chromosomal locations, and their transcriptional changes exhibit significant positive correlations in both primary PCa and castration-resistant prostate cancer (CRPC). One member of this family, APOBEC3C, is demonstrated here as an androgen receptor (AR)-repressed gene. Consistently, APOBEC3 loci are epigenetically inhibited in PCa progression, with APOBEC3C level lower in PSA-high patients. APOBEC3C-low PCa cohorts exhibit increased resistance to Abiraterone and Enzalutamide. Clinicopathological profiling further confirmed APOBEC3C downregulation along PCa progression to advanced phases (grade IV/V, stage III-IV, and pathological stage T3-4), underscoring its prognostic value. Additionally, APOBEC3C expression inversely correlates with PCa relapse and mortality, and low APOBEC3C levels are linked to unfavorable survival. Notably, integrated analyses identified APOBEC3C as the sole RNA-editing gene with significance in both differential expression and PCa prognosis, and APOBEC3C had the best diagnostic performance among 19 genes. Our efforts provide a foundation for further RNA editors research in PCa diagnosis and therapy, and grant APOBEC3C as a candidate tumor suppressor.