EZH2
EZH2
Overview
EZH2 (Enhancer of Zeste Homolog 2) is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), a conserved chromatin-modifying enzyme complex that plays a fundamental role in epigenetic gene regulation. EZH2 functions as a histone methyltransferase, catalyzing the trimethylation of histone H3 at lysine 27 (H3K27me3), a repressive chromatin mark that silences target gene expression. Through this mechanism, EZH2 governs critical biological processes including cell differentiation, proliferation, and stem cell identity. Its activity is tightly regulated during normal development, but dysregulation — through overexpression, gain-of-function mutation, or altered complex stoichiometry — has been broadly implicated in oncogenesis, tumor progression, and therapy resistance across a wide range of malignancies.
Beyond its canonical role in cancer, EZH2 has emerged as a mediator of disease-relevant epigenomic reprogramming in non-malignant contexts, including vascular pathology and metabolic disease. As a druggable epigenetic target, EZH2 has attracted considerable pharmacological interest, with selective inhibitors such as Tazemetostat (the first FDA-approved EZH2 inhibitor) and investigational compounds such as GSK-126 (gsk-2816126) demonstrating therapeutic potential across oncologic and inflammatory indications. Its position at the intersection of the epigenome, immune evasion, cell cycle regulation, and DNA methylation makes EZH2 one of the most extensively studied epigenetic regulators in contemporary biomedical research.
Focus of Latest Publications
Recent publications have continued to position EZH2 as a central epigenetic regulator across diverse disease contexts, with many studies focusing on its role as a therapeutic target rather than a standalone biomarker. In computational work on dengue fever, EZH2 emerged as one of three core genes overexpressed in patients, alongside CXCL10 and EPHB2, and was proposed to participate in host immune regulation and inflammatory responses. Single-cell and immune-infiltration analyses suggested associations with dendritic cells, monocytes, macrophages, and CD4+ and CD8+ T cell subtypes. In hepatocellular carcinoma-related network toxicology analyses of bisphenol A exposure, EZH2 was identified among upregulated hub genes with high diagnostic performance in internal cross-validation, and structural modeling suggested stable BPA binding, although the study emphasized that causal in vivo targeting was not established.
Several recent studies examined pharmacologic inhibition of EZH2 in cancer models. In pancreatic neuroendocrine neoplasms, the EZH2 inhibitor GSK126 suppressed proliferation, induced ferroptosis, and reduced tumor growth in vivo, with mechanistic data implicating inhibition of the PI3K/AKT/mTOR pathway; HMGCS1 was proposed as a mediator of resistance to EZH2 inhibition, and combining GSK126 with everolimus enhanced antitumor effects. In rhabdomyosarcoma, multi-omics analyses linked EZH2-dependent gene silencing to radioresistance, and the EZH2 inhibitor tazemetostat acted as a radiosensitizer in vitro and in vivo, improving clonogenic control, increasing G2/M arrest, and promoting apoptosis. In cutaneous T-cell lymphoma, recurrent progression-associated mutations in EZH2 were reported in a multiomic study of clonal evolution, supporting EZH2 inhibition as a potential therapeutic avenue in therapy-resistant disease.
Other studies connected EZH2 to epigenetic remodeling in nonmalignant or treatment-resistant settings. In diabetes-associated atherosclerosis, EZH2-mediated H3K27 trimethylation was elevated in carotid plaques and aortic endothelium, and EZH2 inhibition with GSK-126 reduced endothelial-to-mesenchymal transition and atherosclerotic burden. In osteosarcoma, cisplatin-induced oxidative stress promoted H3K27me3 accumulation, and EZH2 co-localized and co-immunoprecipitated with YAP, suggesting a role in transcriptional repression that contributed to survival after cisplatin exposure. In castration-resistant prostate cancer, DNMT inhibition was shown to trigger EZH2-dependent H3K27me3 accumulation at the ADAMTS1 locus, and dual targeting of DNMTs and EZH2 reactivated ADAMTS1, degraded collagen-rich stroma, suppressed FAK/MAPK signaling, and reversed immunosuppression.
Mechanistic and drug-development studies further refined the understanding of EZH2 biology. A newly characterized EZH2-selective small molecule, C36, was shown to inhibit PRC2 through a SAM non-competitive allosteric mechanism by binding a pocket involving EZH2 and EED, reducing H3K27 trimethylation and PRC2 target gene expression with low hematotoxicity. Multi-omics analyses also identified direct regulation of IFNB1 by EZH2/PRC2, and C36 combined with anti-PD-1 therapy enhanced antitumor efficacy in a syngeneic lung cancer model. Together, these publications highlight EZH2 as a recurrent node in epigenetic repression, therapy resistance, immune modulation, and combination treatment strategies across cancer and inflammatory disease models.