Activation of SREBP1-mediated lipogenesis by the Epstein-Barr Virus-encoded LMP1 promotes cell proliferation and progression of nasopharyngeal carcinoma.

Research output: Contribution to journalArticle

Authors

  • Angela Kwok-Fung Lo
  • Raymond W-M Lung
  • Lawrence S. Young
  • Chuen-Wai Ko
  • Walter Wei Yeung
  • Wei Kang
  • Ka-Fai To
  • Kwok-Wai Lo

Colleges, School and Institutes

External organisations

  • The Chinese University of Hong Kong
  • University of Warwick

Abstract

Nasopharyngeal Carcinoma (NPC) is closely associated with Epstein‐Barr virus (EBV) infection. The EBV‐encoded latent membrane protein 1 (LMP1), which is commonly expressed in NPC, engages multiple signaling pathways that promote cell growth, transformation and metabolic reprogramming. Here, we report a novel function of LMP1 in promoting de novo lipogenesis. LMP1 increases the expression, maturation and activation of sterol regulatory element‐binding protein 1 (SREBP1), a master regulator of lipogenesis, and its downstream target: fatty acid synthase (FASN). LMP1 also induces de novo lipid synthesis and lipid droplet formation. In contrast, siRNA knockdown of LMP1 in EBV‐infected epithelial cells diminished SREBP1 activation and lipid biosynthesis. Furthermore, inhibition of the mTOR pathway, either through the use of mTOR inhibitors or siRNAs significantly reduced LMP1‐mediated SREBP1 activity and lipogenesis, indicating that LMP1 activation of the mTOR pathway is required for SREBP1‐mediated lipogenesis. In primary NPC tumors, FASN overexpression is common, with high levels correlating significantly with LMP1 expression. Moreover, elevated FASN was associated with aggressive disease and poor survival in NPC patients. Luteolin and fatostatin, two inhibitors of lipogenesis, suppressed lipogenesis and proliferation of nasopharyngeal epithelial cells; effects which were more profound in cells expressing LMP1. Luteolin and fatostatin also dramatically inhibited NPC tumor growth in vitro and in vivo. Our findings demonstrate that LMP1 activation of SREBP1‐mediated lipogenesis promotes tumor cell growth and is involved in EBV‐driven NPC pathogenesis. Our results also reveal the therapeutic potential of utilizing lipogenesis inhibitors in the treatment of locally advanced or metastatic NPC.

Details

Original languageEnglish
JournalJournal of Pathology
Early online date3 Jul 2018
Publication statusE-pub ahead of print - 3 Jul 2018

Keywords

  • Nasopharyngeal Carcinoma, Lipogenesis, Epstein‐Barr virus, LMP1, SREBP1