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

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mTORC2-mediated PDHE1α nuclear translocation links EBV-LMP1 reprogrammed glucose metabolism to cancer metastasis in nasopharyngeal carcinoma.
Oncogene ( IF 6.9 ) Pub Date : 2019-02-11 , DOI: 10.1038/s41388-019-0749-y
Jun Zhang ₁ , Lin Jia ₁ , Tengfei Liu ₁ , Yim Ling Yip ₁ , Wing Chung Tang ₁ , Weitao Lin ₁ , Wen Deng _{1,

2} , Kwok Wai Lo ₃ , Chanping You ₁ , Maria Li Lung _{4,

5} , Hong Lok Lung ₆ , Annie Lai-Man Cheung ₁ , Sai Wah Tsao _{1,

5} , Chi Man Tsang ₁

Affiliation

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.

中文翻译：

mTORC2介导的PDHE1α核易位将EBV-LMP1重新编程的葡萄糖代谢与鼻咽癌的癌转移联系起来。

浸润前鼻咽上皮的EBV感染被认为是鼻咽癌（NPC）发病过程中的一个起始步骤，但其机制仍知之甚少。在这里，我们报告通过EBV编码的LMP1介导的代谢重编程，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，来驱动NPC转移的新机制。从机理上讲，EBV-LMP1增加了IGF1的细胞分泌，从而促进了IGF1R的磷酸化，从而激活mTORC2 / AKT信号传导，从而将葡萄糖代谢与细胞运动联系起来。LMP1表达有助于线粒体PDHE1α在Ser293残基处以磷酸化依赖性方式易位到核中。在功能上核PDHE1α促进Snail启动子上的H3K9乙酰化，从而增强细胞运动性，从而推动癌症转移。重要的是，IGP1 / mTORC2 /PDHE1α/ Snail轴与NPC患者的疾病进展和不良预后显着相关。这项研究强调了EBV-LMP1介导的IGF1-mTORC2-PDHE1α信号传导在NPC发病机制中的功能重要性。

更新日期：2019-02-13

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