SNP rs4381241 promotes renal cell carcinoma progression via the FAF1-HDAC3-PDGFB axis

Background Renal cell carcinoma (RCC) is a highly lethal cancer with limited therapeutic options. Genetic heterogeneity, driven by genomic alterations, plays a key role in tumor progression and resistance to treatment. Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) linked to cancer susceptibility and prognosis. However, the functional mechanisms of these SNPs in regulating RCC development remain unclear. Investigating these SNPs could reveal new therapeutic targets. Methods The functional relevance of the SNP was assessed using EMSA, dual-luciferase reporter assays, and CRISPRa/i to confirm its impact on FAF1 expression. 3C/4C analyses confirmed physical interaction with the FAF1 enhancer region. FAF1 expression was measured in TCGA datasets and RCC tissues using qPCR and Western blot. Gene set enrichment analysis (GSEA) identified PDGFB as a downstream target. Gain- and loss-of-function assays were conducted in RCC cell lines, including CCK-8, wound healing, transwell migration, and colony formation assays, along with in vivo subcutaneous xenograft models. Co-IP, CUT&Tag, and ChIP-qPCR were used to study FAF1's interaction with HDAC3 and its role in PDGFB transcription. Results The SNP rs4381241, in the intronic region of FAF1, acts as an enhancer that regulates FAF1 transcription. The T>C substitution reduces FAF1 expression. In both TCGA data and RCC tissues, FAF1 mRNA and protein levels were lower in tumors compared to adjacent normal tissues, with higher FAF1 levels linked to better prognosis. Functional assays showed that FAF1 overexpression suppressed cell proliferation and migration in vitro, and tumor growth in vivo, confirming its tumor-suppressive role. Mechanistically, FAF1 interacts with HDAC3 to recruit it to the PDGFB promoter, leading to histone deacetylation at H3K9ac and H3K27ac, suppressing PDGFB transcription and inhibiting PDGFRB/PI3K-AKT signaling. Conclusion The intronic SNP rs4381241 is a functional enhancer variant regulating FAF1 expression in RCC. FAF1 suppresses RCC cell proliferation and migration and interacts with HDAC3 to repress PDGFB transcription, inhibiting the PDGFRB/PI3K-AKT pathway. These findings highlight rs4381241 as a key modulator of RCC progression through the FAF1-HDAC3-PDGFB axis. Keywords renal cell carcinoma, rs4381241, FAF1, HDAC3, PDGFB