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.

• Authors: Xiangjian Luo, Liping Hong, Can Cheng, Namei Li, Xu Zhao, Feng Shi, Jikai Liu, Jia Fan, Jian Zhou, Ann M Bode, Ya Cao
• Journal: Cell death & disease (Cell Death Dis) Vol. 9 Issue 6 Pg. 619 (05 23 2018) ISSN: 2041-4889 [Electronic] England
• PMID: 29795311 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• EBV-associated membrane antigen, Epstein-Barr virus
• Terpenes
• Viral Matrix Proteins
• grifolin
• DNA (Cytosine-5-)-Methyltransferase 1
• Glucose

Topics

• Aerobiosis
• Cell Line, Tumor
• DNA (Cytosine-5-)-Methyltransferase 1 (genetics, metabolism)
• Down-Regulation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Glucose (metabolism)
• Glycolysis (drug effects)
• Humans
• Mitochondria (drug effects, metabolism)
• Nasopharyngeal Carcinoma (genetics, metabolism, pathology)
• Oxidative Phosphorylation (drug effects)
• Terpenes (pharmacology)
• Viral Matrix Proteins (metabolism)