Curcumin-Induced DNA Demethylation in Human Gastric Cancer Cells Is Mediated by the DNA-Damage Response Pathway

Figure 5

Proposed model for curcumin-induced DNA demethylation of hGCCs. Curcumin at high concentration elevates the level of intracellular ROS in hGCCs, causing mitochondrial damage (exhibited by the decrease in ), DNA damage, and apoptosis. DNA damage then triggers DDR and recruits ATM/ATR/DNA-PK to strand break sites to repair damaged DNA. ATM/ATR/DNA-PK can phosphorylate both histone γH2AX on chromatin flanking double strain break sites and p53, resulting in the activation of the p53 pathway. This leads to apoptosis, with upregulation of the target genes, p21 and GADD45A. Expressed p21 and GADD45A may then inhibit the combination of cyclin D with CDK4,6 and cyclin E with CDK2 and prevent the phosphorylation of Rb by these cyclin/CDK complexes and, thereby, induce cell cycle arrest. Nonphosphorylated Rb may associate with E2F factors and inhibit the expression of E2F-regulated genes, including Cyclin E and DNMT1. The downregulation of DNMT1 may then lead to DNA demethylation after DNA is replicated in the S phase of the cell cycle.