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

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 c...

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Autores principales: Luo, Xiangjian, Hong, Liping, Cheng, Can, Li, Namei, Zhao, Xu, Shi, Feng, Liu, Jikai, Fan, Jia, Zhou, Jian, Bode, Ann M., Cao, Ya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966399/
https://www.ncbi.nlm.nih.gov/pubmed/29795311
http://dx.doi.org/10.1038/s41419-018-0662-2
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author Luo, Xiangjian
Hong, Liping
Cheng, Can
Li, Namei
Zhao, Xu
Shi, Feng
Liu, Jikai
Fan, Jia
Zhou, Jian
Bode, Ann M.
Cao, Ya
author_facet Luo, Xiangjian
Hong, Liping
Cheng, Can
Li, Namei
Zhao, Xu
Shi, Feng
Liu, Jikai
Fan, Jia
Zhou, Jian
Bode, Ann M.
Cao, Ya
author_sort Luo, Xiangjian
collection PubMed
description 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.
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spelling pubmed-59663992018-05-24 DNMT1 mediates metabolic reprogramming induced by Epstein–Barr virus latent membrane protein 1 and reversed by grifolin in nasopharyngeal carcinoma Luo, Xiangjian Hong, Liping Cheng, Can Li, Namei Zhao, Xu Shi, Feng Liu, Jikai Fan, Jia Zhou, Jian Bode, Ann M. Cao, Ya Cell Death Dis Article 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. Nature Publishing Group UK 2018-05-23 /pmc/articles/PMC5966399/ /pubmed/29795311 http://dx.doi.org/10.1038/s41419-018-0662-2 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Luo, Xiangjian
Hong, Liping
Cheng, Can
Li, Namei
Zhao, Xu
Shi, Feng
Liu, Jikai
Fan, Jia
Zhou, Jian
Bode, Ann M.
Cao, Ya
DNMT1 mediates metabolic reprogramming induced by Epstein–Barr virus latent membrane protein 1 and reversed by grifolin in nasopharyngeal carcinoma
title DNMT1 mediates metabolic reprogramming induced by Epstein–Barr virus latent membrane protein 1 and reversed by grifolin in nasopharyngeal carcinoma
title_full DNMT1 mediates metabolic reprogramming induced by Epstein–Barr virus latent membrane protein 1 and reversed by grifolin in nasopharyngeal carcinoma
title_fullStr DNMT1 mediates metabolic reprogramming induced by Epstein–Barr virus latent membrane protein 1 and reversed by grifolin in nasopharyngeal carcinoma
title_full_unstemmed DNMT1 mediates metabolic reprogramming induced by Epstein–Barr virus latent membrane protein 1 and reversed by grifolin in nasopharyngeal carcinoma
title_short DNMT1 mediates metabolic reprogramming induced by Epstein–Barr virus latent membrane protein 1 and reversed by grifolin in nasopharyngeal carcinoma
title_sort dnmt1 mediates metabolic reprogramming induced by epstein–barr virus latent membrane protein 1 and reversed by grifolin in nasopharyngeal carcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966399/
https://www.ncbi.nlm.nih.gov/pubmed/29795311
http://dx.doi.org/10.1038/s41419-018-0662-2
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