[Multi-omics analysis of the relationship between oxidative stress-related gene and prostate cancer].

[OBJECTIVE] To investigate the relationship between oxidative stress-related genes and prostate cancer (PCa) from a multi-omics perspective using summary-data-based Mendelian randomization (SMR), colocalization analysis, and cellular experiments.

[METHODS] Summary-level data on DNA methylation, gene expression, and circulating proteins were obtained and filtered. The PRACTICAL consortium was used as the discovery cohort, with the deCODE database serving as the validation cohort. SMR analysis and heterogeneity in dependent instruments (HEIDI) tests were conducted to assess the association and heterogeneity between oxidative stress-related genes and PCa. Colocalization analysis was performed to determine whether oxidative stress-related genes and PCa shared common causal variants. Finally, CCK-8 assays, wound healing assays, and Transwell invasion assays and Western blotting, were conducted to examine the effects of oxidative stress-related genes on the biological behavior of the PCa cell line C4-2.

[RESULTS] Multi-omics analysis identified as significantly associated with increased PCa risk across gene methylation, gene expression, and circulating protein levels. showed significant associations at the methylation and protein levels, while was associated at the protein level. At the methylation level, sites cg00581603 (=1.11, 95%: 1.05-1.17) and cg13078931 (=1.12, 95%: 1.05-1.18) were identified as pathogenic. Among the four methylation sites in , only cg05244766 (=0.89, 95%: 0.84-0.95) was considered protective. At the gene expression level, (=1.05, 95%: 1.02-1.07) was also found to be a pathogenic factor. At the circulating protein level, (=2.10, 95%: 1.34-3.29) showed a consistent pathogenic trend. In addition, (=1.16, 95%: 1.07-1.25) and (=1.12, 95%: 1.05-1.19) were significantly associated with increased PCa risk. Further functional assays demonstrated that knockdown of significantly reduced the oncogenic phenotype of prostate cancer cells.

[CONCLUSION] Through integrated multi-omics analysis and experimental validation, this study confirmed a significant association between and increased PCa risk. These findings enhance our understanding of PCa pathogenesis and provide new potential targets and therapeutic directions for PCa treatment.