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

## TL;DR

APOBEC3C helps fight prostate cancer by boosting anti-tumor immunity and controlling cell growth and DNA damage.

## Contribution

APOBEC3C is newly identified as a prostate cancer suppressor through its regulation of inflammation, cell cycle, and DNA damage pathways.

## Key findings

- Low APOBEC3C levels correlate with advanced prostate cancer and worse survival.
- APOBEC3C enhances anti-tumor immunity by increasing CD8+ T cells and reducing M2 macrophages.
- APOBEC3C suppresses cancer cell growth and promotes DNA repair and cell cycle control.

## Abstract

Given the clinical challenge of advanced, therapy-resistant prostate cancer (PCa), this study aimed to identify novel molecular drivers. Using transcriptomic data from the TCGA and GEO databases, combined with WGCNA, differential expression analysis, and LASSO regression, APOBEC3C (A3C) was identified as a key candidate, whose downregulation in PCa tumors correlated with advanced T stage, higher Gleason scores, and poor survival. Bioinformatic analysis linked high A3C expression to an anti-tumor immune microenvironment (e.g., increased CD8+ T cell infiltration and reduced M2 macrophages). In vitro assays confirmed that A3C overexpression suppressed PCa cell proliferation, migration, and invasion, while its knockdown promoted these malignant phenotypes. Mechanistically, A3C enhances the expression levels of STING1 and its downstream molecules, including Caspase1, IL-18, and IL-1β, upregulating DNA damage protective genes (GSTP1 and GPX3) and enhancing cell cycle regulator GAS1 expression. Collectively, this study establishes A3C as a PCa suppressor that impedes tumor progression via multiple key pathways.

Background: 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. Methods: Utilizing transcriptomic data from the TCGA and GEO databases, we identified APOBEC3C (A3C) 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 A3C expression patterns using immunohistochemistry and Western blot in normal and malignant prostate cell lines. The functional effects of A3C 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.). Results:
A3C 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 A3C 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 CD40. In vitro, A3C overexpression effectively suppressed PCa cell proliferation, migration, and invasion, while its knockdown promoted these malignant phenotypes. Mechanistically, A3C enhances the expression of the STING1 and its downstream related molecules Caspase-1, IL-18, and IL-1β; upregulates DNA damage-protective genes (GSTP1 and GPX3); and enhances the expression of cell cycle regulator GAS1. Conclusions: This study establishes A3C as a suppressor in PCa, which impedes tumor progression by regulating key molecules involved in cellular inflammation, cell cycle arrest, and DNA damage response.