MTORC2-mediated PDHE1\u03b1 nuclear translocation links EBV-LMP1 reprogrammed glucose metabolism to cancer metastasis in nasopharyngeal carcinoma

Jun Zhang,Annie Lai-Man Cheung,Chi Man Tsang,Sai Wah Tsao,Hong Lok Lung,Kwok Wai Lo,Yim Ling Yip,Maria Li Lung,Wen Deng,Chanping You,Tengfei Liu,Weitao Lin,Lin Jia,Wing Chung Tang

doi:10.1038/s41388-019-0749-y

Jun Zhang, Annie Lai-Man Cheung + Show 12 more

Open Access

PDF Available

https://doi.org/10.1038/s41388-019-0749-y

Copy DOI

Export

Save

Cite

Abstract
Highlights/Summary
Full-Text PDF
Similar Papers

Abstract

Listen

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.

Highlights

Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Oncogenic viruses commonly interfere with the host metabolic signaling pathways to exert their transformation properties [1]
We further performed the enrichment analysis of these differentially expressed genes (DEG) based on the Gene Ontology Consortium (GO) database [24] and observed a large population of genes are involved in cell metabolism (Fig. 1b)
Using gene set enrichment analysis (GSEA) [15], we observed that genes involved in glycolysis and pyruvate metabolism were statistically enriched in Epstein-Barr virus (EBV)-infected cells supporting a role of EBV infection in metabolic reprogramming (Fig. 1c; Fig. S2A–B)

Summary

Introduction

Oncogenic viruses commonly interfere with the host metabolic signaling pathways to exert their transformation properties [1]. EBV-associated NPC is a special type of head and neck cancer, which is highly invasive and metastatic [6]. LMP1 is a well-characterized oncogene encoded by EBV and has been postulated to play an essential role in NPC pathogenesis [7, 8]. The roles of LMP1 in glycolysis addiction, a common hallmark of cancer, is emerging as an important mediator in NPC pathogenesis and progression [9,10,11,12,13]. The role of EBVLMP1 in modulating metabolic pathways to promote dissemination of tumor cells has not been previously reported

Methods

Results

Conclusion