KDM5C: A dual-edged epigenetic regulator in cancer biology-context-dependent roles and therapeutic implications

Lysine-specific demethylase 5C (KDM5C is a histone demethylase that) serves as a critical epigenetic regulator of H3K4 methylation, with context-dependent roles in cancer progression. While functioning as a tumor suppressor in clear-cell renal cell carcinoma (ccRCC) by maintaining genomic stability and inhibiting HIF signaling, it acts as an oncogenic driver in prostate, breast, and hepatocellular carcinomas by promoting epithelial-mesenchymal transition (EMT), metabolic reprogramming, and chemoresistance. KDM5C orchestrates these opposing functions via interactions with key regulators (ARX, Smad3, and HIF1α) and remodeling of chromatin landscapes to enhance tumor plasticity. Its clinical significance is underscored by therapeutic resistance mechanisms, including CD44 cooperation in pancreatic cancer and HPV E6-mediated lncRNA activation in cervical cancer. Although preclinical studies demonstrate that KDM5C inhibitors can overcome drug tolerance and suppress tumorigenesis, challenges persist in achieving subtype specificity and reducing off-target effects. Beyond oncology, KDM5C dysregulation contributes to Claes-Jensen syndrome and neurodevelopmental disorders, reflecting its pleiotropic functions. Future directions should integrate single-cell omics and targeted inhibitor development to elucidate microenvironmental interactions and enable precision therapies. This synthesis positions KDM5C as a pivotal epigenetic nexus in disease pathogenesis, offering context-dependent therapeutic opportunities.