DNMT1 mediates metabolic reprogramming induced by Epstein–Barr virus latent membrane protein 1 and reversed by grifolin in nasopharyngeal carcinoma

Abstract

Cancer cells frequently adapt fundamentally altered metabolism to support tumorigenicity and malignancy. Epigenetic and metabolic networks are closely interactive, in which DNA methyltransferases (DNMTs) play important roles. Epstein–Barr virus (EBV)-encoded latent membrane protein 1 (EBV-LMP1) is closely associated with nasopharyngeal carcinoma (NPC) pathogenesis because it can trigger multiple cell signaling pathways that promote cell transformation, proliferation, immune escape, invasiveness, epigenetic modification, and metabolic reprogramming. Our current findings reveal for the first time that LMP1 not only upregulates DNMT1 expression and activity, but also promotes its mitochondrial translocation. This induces epigenetic silencing of pten and activation of AKT signaling as well as hypermethylation of the mtDNA D-loop region and downregulation of oxidative phosphorylation (OXPHOS) complexes, consequently, leading to metabolic reprogramming in NPC. Furthermore, we demonstrate that grifolin, a natural farnesyl phenolic compound originated from higher fungi, is able to attenuate glycolytic flux and recover mitochondrial OXPHOS function by inhibiting DNMT1 expression and activity as well as its mitochondrial retention in NPC cells. Therefore, our work establishes a mechanistic connection between epigenetics and metabolism in EBV-positive NPC and provides further evidence for pathological classification based on CpG island methylator phenotype (CIMP) in EBV-associated malignancies. In addition, grifolin might be a promising lead compound in the intervention of high-CIMP tumor types. The availability of this natural product could hamper tumor cell metabolic reprogramming by targeting DNMT1.

Human Cytomegalovirus Alters Host Cell Mitochondrial Function during Acute Infection

“…Defining the metabolic requirements during viral infections has been a growing field of interest over the last decade. Viruses have been shown to influence mitochondrial function directly and indirectly through viral proteins, dysregulated calcium homeostasis, and oxidative stress (24)(25)(26)(27)(28)(29)(30)(31)(32). Interestingly, HCMV-infected cells exhibit many similarities to the Warburg Effect (aerobic glycolysis), first described in cancer cells (33,34).…”

Operation of mitochondrial machinery in viral infection-induced immune responses

“…Using a different strategy, Epstein-Barr virus (EBV)encoded latent membrane protein 1 (EBV-LMP1) induces DNA methyltransferase 1 expression and promotes its mitochondrial translocation. Then, activated DNA methyltransferase 1 causes the activation of AKT signaling and the hypermethylation of the mtDNA D-loop region, leading to a reduction in oxidative phosphorylation complexes [31].…”

PGC1α/CEBPB/CPT1A axis promotes radiation resistance of nasopharyngeal carcinoma through activating fatty acid oxidation

“…Metabolic reprogramming is a common feature of tumor cell and is characterized by disorders of glucose metabolism, tricarboxylic acid (TCA) cycle, lipid metabolism, cholesterol metabolism, glutamate metabolism, one-carbon metabolism and choline metabolism. [1][2][3][4][5] Peroxisome proliferator activated receptor (PPAR) coactivator-1α (PGC1α) is an important transcriptional co-activator in control of mitochondrial function and lipid metabolism, especially fatty acid oxidation (FAO). 6 FAO is the primary pathway for the degradation of fatty acids and it promotes NADPH and ATP production.…”