Effect Of Curcumin On Levels Of DNA Methylation And Histone Acetylation In Human Gastric Cancer Cells

Studies have shown that low concentrations of antioxidants exert anti-oxidative effects,while high concentrations induce pro-oxidative effects,which can increase the level of reactive oxygen species(ROS)in cells,and leading to apoptosis.In addition,high levels of ROS can also affect the epigenetic modification patterns of cells.Curcumin is a natural polyphenol antioxidant isolated from the root of turmeric(Curcuma longa).It can inhibit the proliferation and induce the apoptosis of several types of cancer cells,and lead to genomic DNA demethylation.However,the mechanism of DNA demethylation of cancer cells caused by curcumin treatment and its correlation with cancer cells apoptosis has not been clearly elucidated.Moreover,the effects of curcumin on other types of epigenetic modifications of cancer cells needs to be further addressed.In the present study,human gastric cancer cells(hGCCs)line HGC803 were used as materials.During hGCCs were cultured in vitro,they were treated with different concentrations of curcumin,the effects of curcumin treatment on the proliferation,colony formation,and migration of hGCCs were explored.Then,the mechanism of DNA demethylation in hGCCs caused by curcumin treatment,and its correlation with the apoptosis of was hGCCs systematically and deeply explored at cellular,subcellular,molecular,and epigenetic levels.On this basis,the effect of curcumin treatment on the level of histone acetylation of hGCCs was further measured and the related mechanism was explored.The results show that,curcumin in high concentration had a pro-oxidative effect,and could increase ROS level,caused mitochondrial damage,DNA damage and apoptosis of hGCCs.DNA damage triggered the DDR mechanism,and activated the "damaged DNA repair-p53-p21/GADD45A-cyclin/CDK-Rb/E2F-DNMT1/Cyclin E" axis,leading to the downregulation in the expression of DNA methyltransferases 1(DNMT1)and overall demethylation of genomic DNA.In addition,by measuring the levels of oxidative stress-related indicators malondialdehyde(MDA),catalase(CAT)and reduced glutathione(GSH),it was found that the elevated ROS level caused by curcumin treatment activated the c-Jun N-terminal kinase(JNK)and/or mammalian sterile 20-like kinase 1(MST1)signaling pathways,leading to the phosphorylation of Forkhead box O(FOXOs).Phosphorylated FOXOs were then transported into the nucleus,bound to the promoters of histone deacetylase 1/2(HDAC1/HDAC2),promoting the expression of these two genes,and eventually causing the decrease in the level of histone acetylation in hGCCs,high levels of HDAC1/2 lead to deacetylation of FOXOs which in turn activates FOXOs,forming a positive feedback loop with the latter.The findings of this research provide a theoretical basis for the mechanism of the anticancer effects of curcumin,also contribute to redox epigenetics.