Potential risks of histone deacetylase inhibitors in cancer therapeutics and feasible combination therapeutic strategies.

Histone deacetylase inhibitors (HDACis), such as trichostatin A (TSA), have been recognized as promising anti-cancer agents due to their capacity to restore epigenetic regulation and reactivate tumor suppressor genes. However, emerging evidence indicates that unintended pro-metastatic effects may offset the therapeutic benefits of HDACis. Chen elucidate this paradox, demonstrating that TSA-induced hyperacetylation activates the BRD4/c-Myc/ER-stress axis, thereby promoting epithelial-mesenchymal transition and metastasis in esophageal squamous cell carcinoma (ESCC). Furthermore, they clarify the clinical significance of histone acetylation in the prognostic evaluation of ESCC. Their findings underscore the complexity of epigenetic therapies and highlight the necessity of reevaluating the associated risks and combinatorial therapeutic strategies with HDACi-based treatments. Here, we summarize the potential risks of HDACis therapy and discuss feasible combination therapeutic strategies.