Comprehensive analysis of global histone modification pattern with clinical features and therapeutic potential in...

Glioblastoma (GBM) is a highly aggressive primary brain tumor characterized by profound molecular heterogeneity and poor clinical outcome. Although current prognostic stratification mainly relies on clinicopathological and molecular features, the contribution of histone modification-related programs to GBM progression and therapeutic vulnerability remains insufficiently defined. In this study, we systematically analyzed histone modification patterns in public GBM transcriptomic cohorts and constructed a histone modification-related prognostic signature (HMS). Based on curated histone modification-related pathways and genes, unsupervised clustering identified distinct histone modification subtypes with different biological characteristics. Prognostic genes shared across TCGA-GBM, GSE74187, and GSE83300 were further screened, and LASSO Cox regression was used to establish a nine-gene HMS model. Patients with high HMS scores consistently showed worse survival across independent cohorts, and the HMS remained an independent prognostic factor. Functional enrichment analyses revealed that high-risk tumors were characterized by enhanced extracellular matrix remodeling, epithelial-mesenchymal transition-related programs, immune activation, and immunosuppressive microenvironmental features. High-HMS tumors also exhibited increased immune-cell infiltration and upregulated immune checkpoint molecules, including PD-L1, CTLA-4, PDCD1, and LAG3. TIDE-based analysis suggested potential relevance of the HMS to immune checkpoint blockade response; however, this finding should be interpreted as hypothesis-generating and requires validation in GBM cohorts treated with immunotherapy. ADAMTS4 was identified as a key risk-associated candidate. Functional experiments demonstrated that ADAMTS4 knockdown suppressed GBM cell proliferation, migration, invasion, EMT-related protein expression, and PD-L1/cell-cycle/anti-apoptotic signaling, whereas ADAMTS4 overexpression promoted malignant phenotypes in vitro and accelerated xenograft tumor growth in vivo. Collectively, this study establishes a histone modification-related risk model for GBM and identifies ADAMTS4 as a functional effector linking epigenetic risk stratification with extracellular matrix remodeling, immune regulation, and tumor aggressiveness.