HDAC Inhibitor 4SC-202 Increases Sensitivity to Epirubicin in Liver Cancer Cells by Inhibition of ATM

Abstract Background: Histone deacetylase (HDAC) inhibitors can enhance the anticancer effect of epirubicin in liver cancer. However, the molecular mechanism remains unknown. In our study, we aimed to examine the effect of the combination of HDAC inhibitor 4SC-202 and epirubicin and the underlying mechanism in liver cancer cells. Methods: Cell viability assay, flow cytometry, western blotting, colony formation assay, animal experiment, immunohistochemistry, PCR, and chromatin immunoprecipitation were conducted. Results: We found that 4SC-202 and epirubicin inhibited the growth and induced cell cycle arrest and apoptosis in of HepG2 and Huh7 cells. The combination treatment also reduced tumorigenicity of liver cancer cells in vitro and in vivo. Moreover, 4SC-202 promoted tumor protein D52 (TPD52) transcription and induced TPD52 expression by inhibiting HDAC1/2. TPD52 downregulated ataxia telangiectasia mutated (ATM) expression caused by epirubicin, and liver cancer cells were more sensitive to epirubicin after ATM inhibition. Conclusions: Our results show that 4SC-202 enhances chemosensitivity to epirubicin in liver cancer cells via inhibiting ATM and suggest that the combination may serve as a novel strategy for treatment of liver cancer.