APOBEC3C Suppresses Prostate Cancer by Regulating Key Molecules Involved in Cellular Inflammation, Cell Cycle Arrest, and DNA Damage Response

<b>Background:</b> Prostate cancer (PCa) is a prevalent malignancy with a rising incidence. Advanced PCa, often resistant to therapy, remains a major clinical challenge, underscoring the need to identify novel molecular drivers. <b>Methods:</b> Utilizing transcriptomic data from the TCGA and GEO databases, we identified <i>APOBEC3C (A3C)</i> as a key candidate through WGCNA, differential expression analysis, and LASSO regression. Its clinical relevance was assessed via Kaplan-Meier survival analysis. Then, we validated <i>A3C</i> expression patterns using immunohistochemistry and Western blot in normal and malignant prostate cell lines. The functional effects of <i>A3C</i> on proliferation, migration, and invasion and mechanisms of such were evaluated through in vitro gain- and loss-of-function assays (CCK-8, Ki67 staining, wound healing, Transwell, Western blot, etc.). <b>Results:</b><i>A3C</i> was significantly downregulated in PCa, and this low expression strongly correlated with adverse clinicopathological features, including advanced T stage, higher Gleason scores, and worse survival. Bioinformatically, high <i>A3C</i> expression was associated with an activated anti-tumor immune microenvironment, characterized by enhanced CD8+ T cell infiltration, reduced M2 macrophage abundance, and upregulation of the immune checkpoint <i>CD40</i>. In vitro, <i>A3C</i> overexpression effectively suppressed PCa cell proliferation, migration, and invasion, while its knockdown promoted these malignant phenotypes. Mechanistically, <i>A3C</i> enhances the expression of the <i>STING1</i> and its downstream related molecules <i>Caspase-1</i>, <i>IL-18</i>, and <i>IL-1β</i>; upregulates DNA damage-protective genes (<i>GSTP1</i> and <i>GPX3</i>); and enhances the expression of cell cycle regulator <i>GAS1</i>. <b>Conclusions:</b> This study establishes <i>A3C</i> as a suppressor in PCa, which impedes tumor progression by regulating key molecules involved in cellular inflammation, cell cycle arrest, and DNA damage response.