Opposing outcomes of short- and long-term epigenetic therapy in breast cancer: Implications for chemotherapy response.

Targeting epigenetic modifications has gained considerable attention as a therapeutic approach in cancer, with several epigenetic drugs (Epidrugs) already earned the Food and Drug Administration (FDA) approval. Despite this progress, their clinical application in solid tumors including breast cancer remains limited, emphasizing the importance of optimizing treatment strategies with respect to duration and scheduling. In this study, we evaluated the impact of short- (2 days) and long-term (3 months) exposure to Epidrugs on gene expression and chemosensitivity in breast cancer cells using Tazemetostat (TAZ), an EZH2 inhibitor, alongside the HDAC inhibitor vorinostat and the DNA demethylating agent decitabine. Short-term treatment of TAZ predominantly upregulated pathways associated with stress response, apoptosis, and metabolism, resulting in an enhanced sensitivity to chemotherapeutic agents. In contrast, long-term exposure to TAZ induced complete loss of H3K27me3, extensive transcriptomic reprogramming, and upregulation of pathways related to stemness, metastasis, angiogenesis, and oncogenic signaling, which correlated with reduced chemosensitivity and a drug-resistant phenotype. A similar pattern of short-term sensitization and long-term resistance was observed for vorinostat and decitabine. These findings highlight the critical role of treatment duration in shaping cellular responses to epigenetic therapy and underscore the importance of temporal optimization when combining Epidrugs with conventional cancer therapeutics.