Mechanism Of Grifolin Regulation Nasopharyngeal Carcinoma Glycolysis And Mitochondrial Oxidative Phosphorylation By DNMT1

Metabolism is the set of life-sustaining chemical transformations. It is the one of the important characteristic of life activity. Glucose is the primary source of energy by ATP synthesis. In the presence of oxygen, most differentiated cells primarily metabolize glucose to carbon dioxide by oxidative phosphorylation of glycolytic pyruvate in the mitochondrial to maximize ATP production. It is only under anaerobic conditions that differentiated cells produce large amounts of lactate. The metabolism of glucose to lactate generates only2ATPs per molecule of glucose, it is called glycolysis.Metabolic reprogramming is the key role of carcinogenesis. In most solid tumor cells, a switch in metabolism towards glycolysis over respiration in spite of their functional oxidative phosphorylation machinery manifests the cancer-specific aerobic glycolysis. It involves a metabolic shift from oxidative phosphorylation to glycolysis or lactate fermentation, even in the presence of oxygen.Aerobic glycolysis in cancers is the combined result of oncogenes, tumor suppressor genes, mtDNA. Activate oncogenes or inactivate tumor suppressor genes can significantly affect activities of metabolic enzymes and have a key role in aerobic glycolysis of cancer. The PI3K pathway has frequently been shown to be altered, and it antagonizes the tumor suppressor gene PTEN, the hypermethylation of pten increases glycolysis. mtDNA is regulates mitochondrial function, and mtDNA aberrant methylation is one results in mitochondrial Dysregulation.DNA methylation is regulated by DNA methyltransferases (DNMTs) family that transfer methyl groups from S-adenosyl-L-methionine (SAM) to the5-position of cytosines. This reaction mainly takes place at cytosines when positioned next to a guanine (CpG dinucleotides) and creates5-methylcytosine (5mC) and S-adenosyl-L-homocysteine (SAH).DNA methylation patterns in normal tissues are dependent on the activity of DNMTs, and is a major mechanism for X chromosome inactivation and genomic imprinting. Tumor specific changes in DNA methylation can alter genetic stability, genomic structure, and gene expression. Gene silencing by promoter methylation has been shown for multiple tumor suppressor genes(TSG). Studys show that, DNMT1and DNMT3a/3b are presencetion in mitochondrial, take part in the regulation of mtDNA. DNMT1mitochondrial translocation is regulated by NRF1, which is activated by ROS. Aberrant activation of mtDNMTl leads to mtDNA methylation.Epigenetic alterations have been identified as promising new targets for cancer prevention strategies as they occur early during carcinogenesis and represent potentially initiating events for cancer development.5-azacytidine and5-aza-2-deoxycytidine are the DNMTs inhibitor that approved by FDA, and some natural compounds also reveal the DNMTs inhibitor effect, such as EGCG, caffeic acid, Genistein, Sulforaphane.Grifolin is a secondary metabolite isolated from the fresh fruiting bodies of the mushroom Albatrellus confluens. It has been shown to inhibit the growth of some cancer cell lines in vitro by induction of apoptosis and cell cycle arrest yizin previous studies of our group. Furthermore, we confirm the inhibition of metastasis of grifolin, and elucidated ERK1/2is the grifolin target molecule,it is a novel antitumor agent. We find that DNMT1promoter region has the binding site of Elk-1, which is regulated by ERK1/2.We confirm that, grifolin down-regulates DNMT1both transcription and protein levels, and inhibits glycolysis by recovering the PTEN expression in NPC. Simultaneously, it reduces the level of ROS,inhibits the mitochondrial translocation of DNMT1by NRF1down-regulation. Thereby, oxidative phosphorylation function of mitochondrial is recovered.We find the new function and new mechanism of grifolin inhibition DNMT1, providing evidence of that grifolin is a DNMT1inhibitor.