Integrative multi-omics analysis identifies histone methyltransferase SUV420H2 as a prognostic biomarker in clear...

Renal cell carcinoma (RCC) remains a clinically challenging malignancy characterized by high heterogeneity, limited early biomarkers, and suboptimal response rates to current targeted and immune-based therapies. Increasing evidence highlights that dysregulated epigenetic mechanisms, particularly altered histone methylation, contribute to tumor progression, metabolic reprogramming, and immune escape in RCC. However, the specific regulatory networks linking epigenetic modifiers with transcriptomic rewiring and therapeutic vulnerabilities in clear cell RCC (ccRCC) remain poorly defined. In this multi-omics in silico study, we systematically screened all histone methyltransferases and identified SUV420H2 (also known as KMT5C) as the most consistently overexpressed gene associated with adverse clinical outcomes in ccRCC. SUV420H2 showed stepwise upregulation with tumor stage and grade, while promoter analysis revealed multiple significantly hypomethylated CpG sites, suggesting a potential epigenetic deregulation. Complementarily, six predicted SUV420H2-targeting miRNAs were significantly downregulated in ccRCC consistent with post-transcriptional regulatory control. SUV420H2 overexpression correlated with increased CD4⁺/CD8⁺ T-cell infiltration, indicating an association with altered immune infiltration patterns. Co-expression and enrichment analyses revealed strong associations with chromatin organization, mitotic regulation, RNA metabolic processes, and RNA splicing, from which a five-gene RNA-processing signature (KAT2A, SNRNP70, CCNL2, CLK2, AKAP17A) was derived. This signature was strongly correlated with SUV420H2 and was associated with poorer overall survival specifically in ccRCC. Drug-sensitivity profiling further showed that high SUV420H2/RNA-processing signature expression conferred increased sensitivity to FK866 (NAMPT inhibitor), topoisomerase inhibitors, and apoptosis-inducing agents, identifying potential therapeutic associations that warrant further investigation. Collectively, our findings suggest that SUV420H2 is a multi-layer dysregulated epigenetic regulator associated with ccRCC progression and highlight its RNA-processing network as a promising prognostic and therapeutic axis.