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mTORC2 介导的 PDHE1α 核转位将 EBV-LMP1 重编程的葡萄糖代谢与鼻咽癌中的癌症转移联系起来。

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

机构信息

School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

School of Nursing, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

出版信息

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

DOI:10.1038/s41388-019-0749-y
PMID:30745576
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6756087/
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 Ser 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.

摘要

EBV 感染的癌前鼻咽上皮被认为是鼻咽癌（NPC）发病机制中的起始步骤，但发病机制仍知之甚少。在这里，我们通过 EBV 编码的 LMP1 介导的代谢重编程报告了一种新的机制，通过激活 IGF1-mTORC2 信号和 PDHE1α（一种参与葡萄糖代谢的酶）对 Snail 启动子的核乙酰化，驱动 NPC 转移。在机制上，EBV-LMP1 增加了 IGF1 的细胞分泌，促进 IGF1R 的磷酸化以激活 mTORC2/AKT 信号，将葡萄糖代谢与细胞迁移联系起来。LMP1 表达促进线粒体 PDHE1α 在 Ser 残基上以磷酸化依赖性方式易位到细胞核中。功能上，核 PDHE1α 促进 Snail 启动子上的 H3K9 乙酰化，从而增强细胞迁移性，从而促进癌症转移。重要的是，IGF1/mTORC2/PDHE1α/Snail 轴与 NPC 患者的疾病进展和预后不良显著相关。这项研究强调了 EBV-LMP1 介导的 IGF1-mTORC2-PDHE1α 信号在 NPC 发病机制中的功能重要性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc95/6756087/a0268c8fca25/41388_2019_749_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc95/6756087/1459718b1504/41388_2019_749_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc95/6756087/b627a5098ceb/41388_2019_749_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc95/6756087/0afe827cef77/41388_2019_749_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc95/6756087/37326112e208/41388_2019_749_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc95/6756087/b6f75571fe05/41388_2019_749_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc95/6756087/24ebdcabf6d6/41388_2019_749_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc95/6756087/a0268c8fca25/41388_2019_749_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc95/6756087/1459718b1504/41388_2019_749_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc95/6756087/b627a5098ceb/41388_2019_749_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc95/6756087/0afe827cef77/41388_2019_749_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc95/6756087/37326112e208/41388_2019_749_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc95/6756087/b6f75571fe05/41388_2019_749_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc95/6756087/24ebdcabf6d6/41388_2019_749_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc95/6756087/a0268c8fca25/41388_2019_749_Fig7_HTML.jpg

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