HDAC Inhibitors And DNA Damaging Agents Synergistically Degrade Cellular Histones

Background The anticancer therapies of histone deacetylase(HDAC)inhibitor combined with DNA-damaging agent are currently under clinical investigations,but the underlying mechanism is unclear.Histone homeostasis is critical to cell normal function and cell survival.We have previously demonstrated that the HDAC inhibitor,Trichostatin A(TSA),could promote the degradation of the core histones induced by ?-radiation or DNA-alkylating agent methyl methanesulfonate(MMS)in mouse spermatocytes and embryonic fibroblast cell lines.Methods Cells were treated with HDAC inhibitor TSA,combined with? MMS or the DNA topoisomerase II inhibitor etoposide,and cell death were analyzed by trypan blue exclude.And other HDAC inhibitors and DNA-damaging agents combination also were verified.The expression of histones and ralated proteins were checked by Western blot,which showed the correlation between cell death rate and histone degradation.TUNEL assay was used to determine the effect on apoptosis.Results In this study,we found that the combination treatment of TSA and MMS induced the death of tumor cells with an additive effect.The treatment with TSA in combination with either MMS or etoposide synergistically promoted the degradation of the core histones in tumor cells.Notably,the degradation of the core histones positively correlated with tumor cell death.Meanwhile,we showed that cell cycle arrest might not be a primary consequence for the joint treatment of TSA and MMS.Moreover,the histone degradation preceded the tumor cell death.Conclusions These results suggest that histone degradation underlies the mechanism by which the joint treatment by HDAC inhibitors and DNA-damaging anticancer agents leads to tumor cell death,raising the possibility that the degradation of the core histones serves as a new target for the development of cancer therapy.