Epstein-Barr virus hijacks histone demethylase machinery to drive epithelial malignancy progression through KDM5B upregulation.

Epstein-Barr virus (EBV) is a significant epigenetic driver in the development of epithelial-origin nasopharyngeal carcinoma (NPC) and gastric cancer (GC), which together represent 80% of EBV-associated malignancies. Despite its known association, the specific mechanisms, particularly those involving EBV-induced histone modifications, remain poorly understood. Through integrative analyses of single-cell and bulk transcriptome data from epithelial tumor tissues and EBV-infected cells, we identified KDM5B as a critical histone-modifying factor consistently upregulated following EBV infection. We demonstrated that EBV stimulates KDM5B expression via interactions of its latent gene EBNA1 with transcription factor CEBPB and through direct binding of its lytic gene BZLF1 to Zta-response elements on the KDM5B promoter. Functional assays revealed that KDM5B acts as an oncogene, correlating with poor survival outcomes in EBV-associated epithelial cancers. Mechanistically, KDM5B inhibited the tumor suppressor gene PLK2 through histone demethylation, thereby activating the PI3K/AKT/mTOR signaling pathway and promoting malignant progression. Furthermore, treatment with the KDM5B inhibitor AS-8351 markedly attenuated this signaling activity and exhibited strong anti-tumor effect in both in vitro and in vivo patient-derived xenograft models from EBV-associated tumors. Together, these findings provide novel insights into how EBV hijacks KDM5B to mediate histone demethylation of PLK2, facilitating tumor progression through the PI3K/AKT/mTOR pathway in epithelial cancers, highlighting promising therapeutic strategies targeting epigenetic alterations in EBV-associated cancers.