Integrated transcriptomic and functional analyses of the S100 family support a tumor-suppressive role for S100A14 in prostate cancer

To systematically characterize the S100 family in prostate adenocarcinoma (PRAD) and further evaluate the clinical and functional relevance of S100A14. Bulk transcriptomic, clinical, and single-cell RNA-sequencing data from TCGA and GEO were integrated to characterize S100 family expression, clinical associations, and cell-type distribution. Univariable and multivariable Cox regression analyses were performed to evaluate the prognostic association of S100A14. Reciprocal loss- and gain-of-function experiments, androgen-deprivation modeling, apoptosis assays, and xenograft models were used for functional validation. Multiple S100 family members were downregulated in PRAD, and S100A14 was prioritized for functional investigation based on its expression pattern, favorable prognostic association, and predominant expression in epithelial cells. High S100A14 expression remained significantly associated with a favorable outcome after adjustment for clinicopathological variables (adjusted HR = 0.483, 95% CI: 0.265–0.879, P = 0.017). External GEO cohorts further supported an association between S100A14 expression and biochemical recurrence-free survival. Functional experiments showed that S100A14 suppressed prostate cancer cell proliferation and tumor growth. Its anti-proliferative activity was retained during androgen deprivation, and S100A14 modulation was accompanied by altered apoptotic activity. Our findings extend previous observations of the tumor-suppressive role of S100A14 in prostate cancer and suggest that S100A14 may provide complementary prognostic information alongside established clinicopathological factors. Prospective multicenter validation is required before clinical application.