Ellagic acid: a potential inhibitor of enhancer of zeste homolog-2 and protein arginine methyltransferase-5

Dysregulation of epigenetic processes, characterized by aberrant DNA methylation patterns and histone modifications, is a hallmark of cancer, driving its initiation, progression, and metastasis by silencing tumor suppressor genes or activating oncogenes. Perturbations in histone modifications such as H3K27me3 by EZH2 and H4R3me2s by PRMT5 play significant roles in these epigenetic alterations, disrupting normal gene expression and facilitating oncogene activation while suppressing tumor suppressor genes. Consequently, inhibitors targeting enzymes involved in DNA methylation, histone modification, or chromatin remodeling, such as PRMTs and PRC complexes, are promising anti-cancer agents, with several undergoing pre-clinical and clinical trials. Our screening of a phytochemical library revealed ellagic acid as an effective inhibitor of both EZH2 and PRMT5. Ellagic acid interacts strongly with the EZH2 and PRMT5:MEP50 complex, binding to their active sites through {pi}-cation interactions and hydrogen bonds. Surface Plasmon Resonance study confirmed potent binding affinities of ellagic acid, with KD values of 3.28E-06 and 6.54E-05 for EZH2 and PRMT5:MEP50 respectively. In-vitro assays validated inhibitory effects on EZH2 and PRMT5:MEP50 by reducing the levels of their catalytic products H3K27me3 and H4R3me2s respectively and induction of autophagy and apoptosis. Further In-vivo studies using mouse xenografts further demonstrated significant tumor size reductions upon oral administration of ellagic acid, with decreased expression of the proliferative marker ki67 and histone repressive marks. Taken together we showed that inhibition of EZH2 and PRMT5:MEP50 by ellagic acid could be used to develop breast cancer therapeutic drug.