Epigenetic Modulation in Cancer Pharmacotherapy

Abstract

Epigenetic dysregulation is a hallmark of malignant transformation, offering reversible therapeutic targets distinct from static genomic mutations. This study systematically evaluates the pharmacotherapeutic efficacy of four classes of epigenetic agents -- DNA methyltransferase inhibitors (DNMTi), histone deacetylase inhibitors (HDACi), EZH2 inhibitors, and BET bromodomain inhibitors -- across six solid and haematological cancer models. Using in vitro viability assays (n = 120 cell lines), RNA-seq-based transcriptomic profiling, and chromatin immunoprecipitation sequencing (ChIP-seq), we quantified drug-induced reactivation of silenced tumour suppressor genes (TSGs), global histone modification landscapes, and downstream apoptotic signalling. Combination regimens pairing decitabine with vorinostat produced synergistic growth inhibition (combination index CI = 0.41, p < 0.001) and restored expression of CDKN2A, MLH1, and RASSF1A in 78% of tested cell lines. EZH2 inhibition with tazemetostat reduced H3K27me3 occupancy at TSG promoters by 64% and suppressed colony formation by 71% in lymphoma models. Transcriptomic analysis identified 1,847 differentially expressed genes (DEGs) after dual epigenetic treatment, with pathway enrichment in apoptosis, cell-cycle arrest, and immune checkpoint regulation. These findings establish mechanistic and quantitative frameworks for rational epigenetic combination strategies in oncology, with implications for precision pharmacotherapy design.