Abstract
EBV infection of preinvasive nasopharyngeal epithelium is believed to be an initiation step during pathogenesis of nasopharyngeal carcinoma (NPC), but the mechanisms remain poorly understood. Here we report a novel mechanism driving NPC metastasis through the EBV-encoded LMP1-mediated metabolic reprogramming, via activation of IGF1-mTORC2 signaling and nuclear acetylation of the Snail promoter by the PDHE1α, an enzyme involved in glucose metabolism. Mechanistically, EBV-LMP1 increases the cellular secretion of IGF1 which promotes phosphorylation of IGF1R to activate mTORC2/AKT signaling linking glucose metabolism to cell motility. LMP1 expression facilitates translocation of mitochondrial PDHE1α into the nucleus in a phosphorylation-dependent manner at Ser293 residue. Functionally, nuclear PDHE1α promotes H3K9 acetylation on the Snail promoter to enhance cell motility, thereby driving cancer metastasis. Importantly, the IGF1/mTORC2/PDHE1α/Snail axis correlates significantly with disease progression and poor prognosis in NPC patients. This study highlights the functional importance of IGF1-mTORC2-PDHE1α signaling mediated by EBV-LMP1 in NPC pathogenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / genetics
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Animals
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Cell Nucleus / metabolism*
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Cell Proliferation / genetics
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Cell Transformation, Viral / physiology
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Cells, Cultured
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Epstein-Barr Virus Infections / complications
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Epstein-Barr Virus Infections / genetics
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Epstein-Barr Virus Infections / metabolism
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Glucose / metabolism*
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Glycolysis / genetics
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Herpesvirus 4, Human / physiology
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Humans
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Male
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Mechanistic Target of Rapamycin Complex 2 / physiology*
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Mice
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Mice, Inbred NOD
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Mice, Nude
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Mice, SCID
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Nasopharyngeal Carcinoma / genetics
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Nasopharyngeal Carcinoma / metabolism
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Nasopharyngeal Carcinoma / pathology*
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Nasopharyngeal Carcinoma / virology
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Nasopharyngeal Neoplasms / genetics
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Nasopharyngeal Neoplasms / metabolism
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Nasopharyngeal Neoplasms / pathology*
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Nasopharyngeal Neoplasms / virology
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Neoplasm Metastasis
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Protein Transport
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Pyruvate Dehydrogenase (Lipoamide) / genetics
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Pyruvate Dehydrogenase (Lipoamide) / metabolism*
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Signal Transduction / genetics
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Viral Matrix Proteins / physiology*
Substances
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EBV-associated membrane antigen, Epstein-Barr virus
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Viral Matrix Proteins
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Pyruvate Dehydrogenase (Lipoamide)
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pyruvate dehydrogenase E1alpha subunit
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Mechanistic Target of Rapamycin Complex 2
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Glucose