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.

Key Publications

• NEWJun Unveiling the molecular mechanism of Qingwen Baidu decoction against dengue fever: an integrated study of bioinformatic analysis, machine learning and network pharmacology. (Functional & integrative genomics, 2026, PMID 42332327): "Three core genes, CXCL10, EZH2 and EPHB2 were significantly overexpressed in dengue fever patients, indicating their potential diagnostic and therapeutic value."
• NEWJun Targeting the DNA methylation-H3K27me3 switch reverses castration resistance and immunosuppression via ADAMTS1-driven collagenolysis. (Proceedings of the National Academy of Sciences of the United States of America, 2026, PMID 42313934): "Dual targeting of DNMTs and EZH2 disrupts this epigenetic plasticity, synergistically reactivating ADAMTS1 to degrade collagen-rich stroma, suppress FAK/MAPK mechanotransduction signaling, and reverse epithelial-mesenchymal transition (EMT)."
• NEWJun Allosteric Inhibition of Polycomb Repressive Complex 2 by an EZH2-Selective Small Molecule Inhibitor. (Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2026, PMID 42314051): "Here, we characterized a small molecule C36, which potently inhibits EZH2/PRC2, but not EZH1/PRC2, with a novel SAM non-competitive mechanism."
• Jun Multi-omics analyses identify EZH2 as a central driver in rhabdomyosarcoma radioresistance and highlight Tazemetostat as an effective radiosensitizer in vitro and in vivo. (Cell death & disease, 2026, PMID 42225614): "Emerging evidence implicates EZH2, the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), in promoting RT resistance through gene silencing via H3K27me3."
• May EZH2 inhibition via GSK-126 mitigates EndMT and atherosclerosis in diabetes: A translational epigenetic approach. (Science advances, 2026, PMID 42213823): "the specific role of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, in EndMT in diabetes-associated atherosclerosis remains unclear."
• May Integrating network toxicology with multi-omics approaches to elucidate molecular targets and pathway mechanisms in BPA-induced hepatocellular carcinoma. (Molecular diversity, 2026, PMID 42118483): "Six hub genes (MKI67, CCNA2, EZH2, CCNB1, CDK1, BIRC5) were significantly upregulated in HCC with high internal cross-validated diagnostic accuracy (AUC > 0.96), although these estimates may be susceptible to overfitting and require external validation."
• May HMGCS1 as a potential mediator of resistance to EZH2 inhibition via ferroptosis mediated by PI3K/AKT/mTOR pathway in the pancreatic neuroendocrine neoplasms. (Endocrine-related cancer, 2026, PMID 42013002): "However, the role and mechanisms of EZH2 in pancreatic neuroendocrine neoplasms (pNENs) remain unclear."
• May Cisplatin-Induced Oxidative Stress Regulates YAP to Modulate Epigenome Promoting the Survival of Osteosarcoma Cells. (Biochemistry, 2026, PMID 41980058): "Mechanistically, YAP was found to colocalize and coimmunoprecipitate with EZH2, the catalytic member of the Polycomb Repressive Complex 2 (PRC2), suggesting a potential role for YAP in facilitating EZH2-mediated transcriptional repression."
• May Multiomic study of cutaneous T-cell lymphoma reveals single-cell clonal evolution in progression and therapy resistance. (Blood, 2026, PMID 41662591): "Recurrent progression-associated mutations were common in the epigenetic modifier EZH2, suggesting that EZH2 inhibition may benefit patients with CTCL."