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.
Highlights
Introduction EpsteinBarr virus (EBV) is the first human oncogenic virus that contributes to a wide variety of malignancies of both lymphoid and epithelial origin, such as Burkitt’s and Hodgkin’s lymphomas, nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC)[1]
CNE1 and CNE1LMP1 cells were treated with 13C6-D-glucose for 2 h and extracted metabolites were applied for metabolome analysis by Gas chromatography/Mass spectrometer (GC/MS)
We found that 13C-labeled pyruvate and lactate levels were markedly elevated, whereas 13C-labeled metabolite levels of the tricarboxylic acid cycle, such as 13C-citrate, 13C-α-ketoglutarate, 13C-fumarate, or 13Cmalate, were significantly decreased in CNE1-LMP1 cells compared to CNE1 cells (Fig. 1e)
Summary
Barr virus (EBV) is the first human oncogenic virus that contributes to a wide variety of malignancies of both lymphoid and epithelial origin, such as Burkitt’s and Hodgkin’s lymphomas, nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC)[1]. EBV infection is characterized by the expression of latent genes including Epstein–Barr nuclear antigens Official journal of the Cell Death Differentiation Association. Luo et al Cell Death and Disease (2018)9:619 protein (EBNA-LP)), latent membrane proteins LMP1 and LMP2 and the non-coding EBV-encoded RNAs (EBERs) and viral microRNA (miRNA)[1]. CIMP is defined as the high activity of global and nonrandom CpG island methylation. EBV infection is an epigenetic driver and closely associated with CIMP1,3,11. CpG island promoter methylation of tumor suppressor genes is one of the most characteristic abnormalities in EBV-associated malignancies[12,13,14]. The unbiased genomescale analysis of NPC methylome displayed a high-degree
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