HDAC Inhibition by Trichostatin A in U266 Multiple Myeloma: Anti-Proliferative Effects, Transcriptomic Dysregulation, Core Gene Clusters, and Survival-Associated Biomarkers
DOI:
https://doi.org/10.31436/imjm.v25i02.3375Keywords:
Multiple Myeloma, Trichostatin A (TSA), Histone Deacetylase Inhibitor (HDACi), Transcriptomic Dysregulation, Survival-Associated BiomarkersAbstract
INTRODUCTION: Histone deacetylases (HDACs) regulate chromatin and gene expression, and their dysregulation contributes to multiple myeloma (MM). This study evaluated the epigenetic effects of the HDAC inhibitor Trichostatin A (TSA) on U266 MM cells, its impact on proliferation, transcriptomic alterations, core gene clusters, and association with MM survival. MATERIALS AND METHODS: U266 cells were treated with TSA and assessed by MTT assays to determine IC₅₀ values. Cell cycle arrest and apoptosis were measured by flow cytometry. RNA-Seq identified differentially expressed genes, followed by KEGG analysis. PPI networks and core gene clusters were generated using STRING and Cytoscape MCODE, and Kaplan-Meier plots evaluated their associations with survival outcomes. RESULTS: TSA induced dose-dependent cytotoxicity (IC₅₀ =54.46±4.0 nM) and triggered significant G₀/G₁ arrest (82.98±1.99%), reduced S-phase (9.02±1.99%), and early and late apoptosis rates increased (24.88±2.08% and 24.86±3.81%, respectively. Transcriptomic analysis revealed enriched KEGG pathways including ECM receptor interaction (q=2.05×10⁻⁴), microRNAs in cancer (q=7.52×10⁻⁴), and cell cycle (q=9.05×10⁻⁴). Three core gene clusters emerged: Cluster 1 (seed gene OASL; includes IFI44, RSAD2, IFIT3, MX1, IFIT1, IFI44L, XAF1, IFI6), Cluster 2 (NRCAM; includes SPTBN4, SPTA1, ANK1), and Cluster 3 (LRP1; includes APOE, LRP2). APOE upregulation was most strongly correlated with improved survival (log rank p<1×10⁻¹⁶), with RSAD2, XAF1, IFIT1, and SPTBN4 also significant (p≤0.05). CONCLUSION: TSA exerts potent anti-proliferative effects in U266 MM cell line via several mechanisms. Survival-associated core genes Apolipoprotein E (APOE) and Radical S-Adenosyl Methionine Domain Containing 2 (RSAD2) have potential as candidate survival-associated biomarkers and therapeutic targets warrant further validation.
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