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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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