RNF115 upregulation by YBX1-dependent m5C modification promotes hepatocellular carcinoma progression

AbstractOur transcriptome-wide profiling revealed significant heterogeneity in m5C modification patterns across hepatocellular carcinoma (HCC), with differentially methylated genes broadly distributed throughout the genome except chromosome Y. The m5C reader protein YBX1 was significantly upregulated in HCC tissues and correlated with poor prognosis. Through integration of m5C MeRIP-seq and YBX1 RIP-seq data, we identified RNF115 as a direct YBX1 target regulated in an m5C-dependent manner. Mechanistically, YBX1 binds to m5C-modified motifs within RNF115 mRNA 3'UTR, enhancing its stability and translation. RNF115 overexpression was associated with advanced tumor stage, increased metastasis, and poor clinical outcomes. Further investigations demonstrated that the YBX1/m5C-RNF115 axis promotes HCC progression primarily via PI3K/AKT pathway activation. These findings elucidate a novel epitranscriptomic mechanism whereby YBX1 drives HCC malignancy through m5C-dependent RNF115 stabilization, highlighting this axis as a promising therapeutic target.