| Autor: |
Zhang, Jun, Jia, Lin, Liu, Tengfei, Yip, Yim Ling, Tang, Wing Chung, Lin, Weitao, Deng, Wen, Lo, Kwok Wai, You, Chanping, Lung, Maria Li, Lung, Hong Lok, Cheung, Annie Lai-Man, Tsao, Sai Wah, Tsang, Chi Man |
| Zdroj: |
Oncogene; June 2019, Vol. 38 Issue: 24 p4669-4684, 16p |
| Abstrakt: |
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 Snailpromoter 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 Ser293residue. Functionally, nuclear PDHE1α promotes H3K9 acetylation on the Snailpromoter 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. |
| Databáze: |
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