mTORC2-mediated PDHE1α nuclear translocation links EBV-LMP1 reprogrammed glucose metabolism to cancer metastasis in nasopharyngeal carcinoma

Oncogene. 2019 Jun;38(24):4669-4684. doi: 10.1038/s41388-019-0749-y. Epub 2019 Feb 11.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / genetics
  • Animals
  • Cell Nucleus / metabolism*
  • Cell Proliferation / genetics
  • Cell Transformation, Viral / physiology
  • Cells, Cultured
  • Epstein-Barr Virus Infections / complications
  • Epstein-Barr Virus Infections / genetics
  • Epstein-Barr Virus Infections / metabolism
  • Glucose / metabolism*
  • Glycolysis / genetics
  • Herpesvirus 4, Human / physiology
  • Humans
  • Male
  • Mechanistic Target of Rapamycin Complex 2 / physiology*
  • Mice
  • Mice, Inbred NOD
  • Mice, Nude
  • Mice, SCID
  • Nasopharyngeal Carcinoma / genetics
  • Nasopharyngeal Carcinoma / metabolism
  • Nasopharyngeal Carcinoma / pathology*
  • Nasopharyngeal Carcinoma / virology
  • Nasopharyngeal Neoplasms / genetics
  • Nasopharyngeal Neoplasms / metabolism
  • Nasopharyngeal Neoplasms / pathology*
  • Nasopharyngeal Neoplasms / virology
  • Neoplasm Metastasis
  • Protein Transport
  • Pyruvate Dehydrogenase (Lipoamide) / genetics
  • Pyruvate Dehydrogenase (Lipoamide) / metabolism*
  • Signal Transduction / genetics
  • Viral Matrix Proteins / physiology*

Substances

  • EBV-associated membrane antigen, Epstein-Barr virus
  • Viral Matrix Proteins
  • Pyruvate Dehydrogenase (Lipoamide)
  • pyruvate dehydrogenase E1alpha subunit
  • Mechanistic Target of Rapamycin Complex 2
  • Glucose