Epigenetic Remodeling Through GSK343-induced EZH2 Inhibition Alters SMYD2/SMYD3 Expression and Promotes Antitumor Effects.

Epigenetic and Non-Epigenetic Functions of EZH2 in Tumor Development: Structural Basis, Signaling Network, and Targeted Intervention Strategies.

Enhancer of Zeste Homolog 2 (EZH2) is a histone methyltransferase that catalyzes the methylation of histone H3 lysine 27, a modification frequently dysregulated in various cancers. EZH2 plays critical roles in cell proliferation, differentiation, and gene silencing, and its abnormal overexpression is closely associated with tumor aggressiveness and poor prognosis. Inhibiting EZH2 can reactivate tumor suppressor genes and thereby suppress cancer cell growth and metastasis. Although several EZH2 inhibitors, including small molecules and nucleic acid drugs, have been developed and some have entered clinical trials, their specificity and potency still require further optimization. Tazemetostat is the first FDA-approved EZH2 inhibitor for relapsed or refractory follicular lymphoma, while other agents such as EPZ-6438 and GSK126 show promising preclinical antitumor activity. This review summarizes the association between EZH2 and tumors, and the mechanisms and pharmacological properties of EZH2 inhibitors. Future research directions and challenges are also discussed to facilitate the development of EZH2-targeted anticancer therapies strategies.

Pharmacological inhibition of BUB1 suppresses UCEC progression by modulating the PI3K-AKT pathway and reversing anoikis resistance and immune evasion: a multi-omics and experimental study

BUB1 was significantly upregulated in UCEC tumors compared with normal endometrium, associated with advanced disease stage and reduced overall survival, confirming its role as an unfavorable prognostic biomarker and therapeutic target in UCEC.

GATA6-mediated transcriptional activation and METTL3/IGF2BP2-dependent post-transcriptional stabilization upregulate CDC20 to promote the malignant progression of colorectal cancer and immune escape

Protein Arginine Methyltransferase-5 Inhibition Induces Growth Arrest and Death in Triple-Negative Breast Cancer Cells

Background: PRMT5, or protein arginine methyltransferase 5, is recognized as an epigenetic regulator that suppresses gene transcription through symmetric dimethylation of histone arginine residues, including histone H4 arginine 3 (H4R3me2s) and histone H3 arginine 8 (H3R8me2s), modifications associated with chromatin condensation and transcriptional repression. PRMT5-mediated methylation has been associated with recruitment of polycomb repressive complex 2 (PRC2) and enhancer of zeste homolog 2 (EZH2)-mediated H3K27me3 deposition, contributing to stable repression of tumor suppressor genes and apoptosis-related effectors in breast cancer. Methods: The molecular and functional impacts of PRMT5 inhibition were studied in TNBC cell lines with a pharmacological inhibitor (CMP5). Cellular responses were evaluated using a viability assay, qPCR, Western blotting, Annexin V/PI staining, and transwell migration/proliferation assays. Results: PRMT5 inhibition substantially reduced TNBC viability in a time- and dose-dependent manner. EZH2 was downregulated, whereas the tumor suppressor retinoblastoma-like protein 2 (RBL2) was induced, concomitant with low expression of Cyclin D1. These changes were accompanied by upregulation of pro-apoptotic effectors (Caspase-3, Caspase-10, death-associated protein 1 (DAP1), and BCL2-associated x protein (BAX) and repression of the pro-survival B-cell lymphoma 2 (BCL2), consistent with apoptosis-associated molecular responses. Functionally, CMP5 treatment was associated with reduced migratory behavior in TNBC cells under the experimental conditions tested. Conclusions: These findings suggest that PRMT5 inhibition by CMP5 is associated with reduced TNBC cell viability, impaired migration, increased expression of apoptosis-associated regulators and enhanced apoptotic cell death as measured by Annexin V/PI analysis in vitro. Further mechanistic and in vivo studies are required to clarify the therapeutic relevance of PRMT5 inhibition in TNBC.

TET1-mediated DNA demethylation and transcription activation of MRPS17 induces lung adenocarcinoma through PI3K-AKT-mTOR pathway

Lung adenocarcinoma (LUAD), characterized by its complex molecular heterogeneity and resistance to both conventional and targeted therapies, poses significant therapeutic challenges. Therefore, the identification of novel molecular targets is crucial for enhancing therapeutic strategies and improving patient outcomes. This study investigates the role of mitochondrial ribosomal protein S17 (MRPS17) in the progression of LUAD, with a specific focus on its interaction with the PI3K-AKT-mTOR signaling pathway. We conducted functional assays to assess cell proliferation, migration, invasion, and apoptosis in MRPS17-manipulated LUAD cell lines. Further, we explored the epigenetic regulation by TET1 through methylation analysis and investigated the downstream effects on the PI3K-AKT-mTOR pathway using Western blotting and reporter assays. Analysis revealed that MRPS17 is upregulated in LUAD tissues and is associated with a poor prognosis. In cellular models, MRPS17 overexpression was shown to promote proliferation, migration, and invasion, whereas its knockdown induced apoptosis and diminished tumorigenic capabilities both in vitro and in vivo. Importantly, TET1 was identified as a crucial regulator of MRPS17, acting through the demethylation of its promoter to enhance MRPS17 expression and subsequently activate the PI3K-AKT-mTOR pathway. MRPS17 significantly contributes to LUAD progression by enhancing tumor aggressiveness through the PI3K-AKT-mTOR pathway. The TET1-mediated demethylation of MRPS17 introduces a novel epigenetic mechanism that could be leveraged for targeted therapeutic interventions. This study not only provides foundational insights into the molecular biology of LUAD but also highlights the potential of MRPS17 as a prognostic marker and therapeutic target.

Histone deacetylase activity limits the response to EZH2 inhibition-based therapy in epithelioid sarcoma and is targetable by epigenetic combination