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

TitlemTORC2-mediated PDHE1α nuclear translocation links EBV-LMP1 reprogrammed glucose metabolism to cancer metastasis in nasopharyngeal carcinoma
Authors
Issue Date2019
PublisherSpringer Nature [academic journals on nature.com]: Hybrid Journal. The Journal's web site is located at http://www.nature.com/onc
Citation
Oncogene, 2019, v. 38 n. 24, p. 4669-4684 How to Cite?
AbstractEBV 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.
Persistent Identifierhttp://hdl.handle.net/10722/271922
ISSN
2017 Impact Factor: 6.854
2015 SCImago Journal Rankings: 4.047
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorZhang, J-
dc.contributor.authorJia, L-
dc.contributor.authorLiu, T-
dc.contributor.authorYip, YL-
dc.contributor.authorTang, WC-
dc.contributor.authorLin, W-
dc.contributor.authorDeng, W-
dc.contributor.authorLo, KW-
dc.contributor.authorYou, C-
dc.contributor.authorLung, ML-
dc.contributor.authorLung, HL-
dc.contributor.authorCheung, ALM-
dc.contributor.authorTsao, SW-
dc.contributor.authorTsang, CM-
dc.date.accessioned2019-07-20T10:32:09Z-
dc.date.available2019-07-20T10:32:09Z-
dc.date.issued2019-
dc.identifier.citationOncogene, 2019, v. 38 n. 24, p. 4669-4684-
dc.identifier.issn0950-9232-
dc.identifier.urihttp://hdl.handle.net/10722/271922-
dc.description.abstractEBV 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.-
dc.languageeng-
dc.publisherSpringer Nature [academic journals on nature.com]: Hybrid Journal. The Journal's web site is located at http://www.nature.com/onc-
dc.relation.ispartofOncogene-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titlemTORC2-mediated PDHE1α nuclear translocation links EBV-LMP1 reprogrammed glucose metabolism to cancer metastasis in nasopharyngeal carcinoma-
dc.typeArticle-
dc.identifier.emailJia, L: ljia@hku.hk-
dc.identifier.emailYip, YL: yimling@hku.hk-
dc.identifier.emailTang, WC: wtwilson@hku.hk-
dc.identifier.emailDeng, W: wdeng@hku.hk-
dc.identifier.emailLung, ML: mlilung@hku.hk-
dc.identifier.emailLung, HL: hllung2@hku.hk-
dc.identifier.emailCheung, ALM: lmcheung@hku.hk-
dc.identifier.emailTsao, SW: gswtsao@hku.hk-
dc.identifier.emailTsang, CM: annatsan@hku.hk-
dc.identifier.authorityDeng, W=rp01640-
dc.identifier.authorityLung, ML=rp00300-
dc.identifier.authorityLung, HL=rp00299-
dc.identifier.authorityCheung, ALM=rp00332-
dc.identifier.authorityTsao, SW=rp00399-
dc.identifier.authorityTsang, CM=rp01964-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1038/s41388-019-0749-y-
dc.identifier.pmid30745576-
dc.identifier.scopuseid_2-s2.0-85061394974-
dc.identifier.hkuros299026-
dc.identifier.volume38-
dc.identifier.issue24-
dc.identifier.spage4669-
dc.identifier.epage4684-
dc.identifier.isiWOS:000471160500002-
dc.publisher.placeUnited Kingdom-

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