EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit)

Virtual screening and molecular dynamics simulations identified acetyldigitoxin (ADT) as a potent EZH2 inhibitor, demonstrating superior binding affinity (-10.90 kcal/mol) and complex stability compared to the known inhibitor GSK126...ADT induced G0/G1 cell cycle arrest and promoted apoptosis, accompanied by upregulation of pro-apoptotic genes (Bax, Caspase-3) and downregulation of anti-apoptotic (Bcl-2) and cell cycle (CyclinD1) genes. Our integrated findings position ADT as a repurposed drug candidate for targeting EZH2 in NSCLC, warranting further preclinical investigation including direct enzyme inhibition assays.

Functionally, MEP exposure enhanced malignant behaviors in MCF-7 cells and increased CCNE1, CDK1, E2F1, and EZH2 expression. Collectively, this integrated analysis indicates that MEP may promote BRCA development by acting on four central regulators within fibroblasts, providing mechanistic insights into the environmental origins of BRCA.

Consistently, depletion of ADAR1 dramatically enhances the sensitivity of cancer cells and tumors to EZH2 selective degraders. Collectively, our study sheds new light on a link between two layers of epigenetic regulations at histone modification and RNA editing levels, demonstrates a previously uncharacterized role of EZH2 in RNA editing and mRNA stability independently of its lysine methyltransferase activity, and reveals the significance of EZH2-ADAR1 cascade in governing RNA editing and mRNA stability, which may provide additional perspectives for the advancement of EZH2-targeting cancer therapies.

The study developed EIP103 as a first-in-class peptide degrader that targets EZH2 through multivalent, high-affinity interactions and induces conformational destabilization, representing a mechanism distinct from that of the small molecule inhibitor EPZ-6438...Additionally, molecular dynamics (MD) simulations and biochemical assays revealed that the peptide EIP103 binds to the SET domain of EZH2, altering its structure and triggering proteasomal degradation via Praja Ring Finger Ubiquitin Ligase 2 (PJA2)-mediated ubiquitination. Harboring both enzymatic inhibition and post-translational regulation properties, EIP103 exerts durable efficacy and activates antitumor immunity, making it a promising therapeutic candidate for TNBC.

An 80-year-old woman with relapsed nodal T-follicular helper cell lymphoma, not otherwise specified, developed severe watery diarrhea during valemetostat therapy...To the best of our knowledge, this is the first reported case of enhancer of zeste homolog 1 and 2 (EZH1/2) inhibitor-induced colitis. EZH1/2 inhibition may lead to T cell-mediated intestinal injury through epigenetic dysregulation; therefore, patients receiving EZH1/2 inhibitors who develop persistent diarrhea should undergo early endoscopic and histological evaluations.

Dual targeting of Wnt/β-catenin and EZH2 diminishes diverse cell states through restoring bivalency and effectively block tumor growth. Our findings provide unexpected insights of chromatin bivalency and dysregulated circadian rhythm in control of cell state diversity and offer alternative therapeutic strategies targeting PRC2/EZH2 for advanced malignancies.

P1, N=48, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

Using elesclomol-copper complex treatment, a cuproptosis model in HCT116 and RKO CRC cell lines was established...Tumors with elevated EZH2-NEAT1 expression may be particularly sensitive to copper-based therapies. This study establishes EZH2-NEAT1 expression as a potential biomarker for patient selection in cuproptosis-based cancer treatment, though the concurrent effects on tumor migration highlight complex therapeutic considerations for combination treatment strategies.

And intraperitoneal administrating the inhibitor of EZH2 with GSK126 significantly ameliorated the nephritis in MRL/lpr mice. This research reveals a novel epigenetic regulation of JAM-A by EZH2-DNMT3A cascade contributes to T cell adhesion capacity via the activation of Rap1a/β1-integrin in lupus patients.

Melanoma A375 (vemurafenib [VEM]-sensitive) and A375R (VEM-resistant) cells were exposed to eIF4Fi RocA at varying doses and durations in vitro...Combined CR-1-31-B, EZH2i, and AKT1i effectively overcame resistance to RocA and VEM resistance both in vitro and in vivo. The eIF4F complex inhibitor reactivates ERK1/2-EZH2 and AKT1 signaling pathways, resulting in resistance to both eIF4Fi and VEM. Combined administration of an eIF4Fi with EZH2 and AKT1 inhibitors effectively enhances sensitivity to both eIF4F complex and BRAF inhibitors.