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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.

SUBMITTER: Luo X

PROVIDER: S-EPMC5966399 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

Luo Xiangjian X Hong Liping L Cheng Can C Li Namei N Zhao Xu X Shi Feng F Liu Jikai J Fan Jia J Zhou Jian J Bode Ann M AM Cao Ya Y

Cell death & disease 20180523 6

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, ...[more]

PMID: 29795311

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Project description:Transporter associated with antigen processing 2 (Tap-2) is responsible for ATP-dependent transport of peptides from the cytosol to the endoplasmic reticulum, where peptides bind to newly synthesized human leukocyte antigen (HLA) class I molecules, which are essential for cellular immune responses. Epstein-Barr virus (EBV) latent membrane protein 1 (LMP-1) has been shown to induce the expression of Tap-2. In this study, the induction of endogenous Tap-2 by LMP-1 is shown to be associated with and requires the expression of interferon regulatory factor 7 (IRF-7). In DG75 Burkitt's lymphoma (BL) cells, in which LMP-1 induces the expression of IRF-7, LMP-1 induced endogenous Tap-2, and ectopic expression of IRF-7 could enhance the induction. In Akata BL cells, in which LMP-1 could not induce IRF-7, LMP-1 could not induce Tap-2. Addition of IRF-7, which complements the defect in Akata cells, could stimulate the expression of Tap-2. Furthermore, LMP-1 and IRF-7A but not other IRF-7 splicing variants could activate endogenous Tap-2. A Tap-2 promoter reporter construct could be activated by the overexpression of IRF-7A. The activation could be specifically enhanced by LMP-1 and was dependent on an intact interferon-stimulated response element (ISRE) present in the Tap-2 promoter. Also, IRF-7 can bind to the Tap-2 promoter under physiological conditions in vivo, as shown by formaldehyde cross-linking, as well as to the Tap-2 ISRE in vitro, as shown by gel mobility shift assays. Furthermore, LMP-1 facilitates the phosphorylation and nuclear translocation of IRF-7. These data point to the role of IRF-7 as a secondary mediator of LMP-1-activated signal transduction for Tap-2 as follows: LMP-1 stimulates the expression of IRF-7 and facilitates its phosphorylation and nuclear translocation, and then the activated IRF-7 mediates the activation of the cellular Tap-2 gene. The induction of Tap-2 by IRF-7 and LMP-1 may have an important implication for the immune response to EBV and its persistence in vivo.

Dataset Information

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

Publications

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

Similar Datasets

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