Epigenetic potentiation of 5-fluorouracil by HDAC inhibitor quisinostat enhances antitumor effects in colorectal cancer

Histone deacetylase (HDAC) inhibitors have emerged as promising epigenetic therapeutics in cancer treatment; however, their clinical efficacy in solid tumors remains limited. Quisinostat is a potent pan-HDAC inhibitor with demonstrated anticancer activity in various malignancies. This study evaluates the therapeutic potential of Quisinostat, in combination with 5-fluorouracil (5-FU), in colorectal cancer (CRC) cell lines. The effects of Quisinostat and 5-FU, as monotherapies and in combination, were investigated in HCT-116 and HT-29 CRC cell lines. H3K27 acetylation levels were assessed by immunofluorescence to evaluate epigenetic modulation. Cell viability, IC50 shifts, and proliferation were measured using resazurin assays and Ki-67 staining. Apoptosis and mitochondrial membrane potential (ΔΨm) were analyzed via Hoechst 33342/PI dual staining and JC-1 assays. Migration and epithelial-mesenchymal transition (EMT) phenotypes were evaluated through wound healing assays and E-cadherin/N-cadherin immunostaining. Quisinostat significantly increased H3K27 acetylation and enhanced the cytotoxic effect of 5-FU by lowering its IC50 in both cell lines. The combination treatment markedly suppressed proliferation, as evidenced by reduced Ki-67 expression. Quisinostat in combination with 5-FU significantly enhanced ΔΨm loss and apoptotic cell death. Furthermore, the combination treatment inhibited cell migration and reversed the EMT phenotype by increasing E-cadherin and decreasing N-cadherin expression. Quisinostat enhances the antitumor efficacy of 5-FU in CRC cells by promoting histone acetylation, augmenting cytotoxic and apoptotic responses, and reversing EMT-associated migratory phenotypes. These findings support the potential of Quisinostat as an effective adjunct to 5-FU-based chemotherapy in CRC.