SETD8 promotes ovarian clear cell carcinoma by epigenetically activating RNA metabolism genes via H4K20me1.

Ovarian clear cell carcinoma (OCCC) is a chemoresistant subtype of epithelial ovarian cancer with limited therapeutic options and distinct molecular features. Histone methyltransferase SETD8 catalyzes the monomethylation of histone H4 at lysine 20 (H4K20me1) and has been implicated in transcriptional regulation across multiple cancer types. In endometrial cancer, we previously demonstrated that SETD8 regulates downstream targets through integrative ChIP-seq and RNA-seq analyses, linking its activity to p53-dependent signaling pathways. However, the role of SETD8 in OCCC and its potential tumor-context–specific functions remain undefined. Integrative analyses of ChIP-seq and RNA-seq in OCCC revealed that SETD8 maintains the expression of genes critical for RNA processing, including HNRNPA2B1, EIF4G1, and SRSF3, in a manner independent of p53 signaling. Pharmacological inhibition or RNA interference–mediated depletion of SETD8 resulted in a pronounced reduction of global H4K20me1 levels, impaired cellular proliferation, and increased lipid peroxidation consistent with ferroptotic stress. Transcriptomic profiling further demonstrated that SETD8 inhibition reprograms ferroptosis-associated gene expression, establishing a mechanistic link between chromatin-based transcriptional control and cellular redox vulnerability. Furthermore, clinical data analysis from public datasets (GSE29450 and TCGA-KIRC) confirmed that SETD8 is significantly overexpressed in OCCC tissues compared to normal counterparts and that high SETD8 expression correlates with poor overall survival in clear cell lineage tumors, underscoring its potential as a clinical biomarker. Our study provides an in vitro mechanistic framework in which SETD8 safeguards RNA metabolic integrity and mitigates ferroptotic stress through epigenetic regulation in OCCC. These results underscore the lineage-specific roles of SETD8 across gynecologic malignancies and identify SETD8 as a potential therapeutic vulnerability that warrants further in vivo investigation.