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Hypoxia-inducible factor-1α plays roles in Epstein-Barr virus’s natural life cycle and tumorigenesis by inducing lytic infection through direct binding to the immediate-early BZLF1 gene promoter
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Document Title
Hypoxia-inducible factor-1α plays roles in Epstein-Barr virus’s natural life cycle and tumorigenesis by inducing lytic infection through direct binding to the immediate-early BZLF1 gene promoter
Author
Kraus R.J.,Yu X.,Cordes B.-L.A.,Sathiamoorthi S.,Iempridee T.,Nawandar D.M.,Ma S.,Romero-Masters J.C.,McChesney K.G.,Lin Z.,Makielski K.R.,Lee D.L.,Lambert P.F.,Johannsen E.C.,Kenney S.C.,Mertz J.E.
Name from Authors Collection
Affiliations
McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, United States; National Nanotechnology Center, National Science and Technology Development Agency Science Park, Pathum Thani, Thailand; Department of Pathology, Tulane University Health Sciences Center and Tulane Cancer Center, New Orleans, LA, United States; Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, United States
Type
Article
Source Title
PLoS Pathogens
ISSN
15537366
Year
2017
Volume
13
Issue
6
Open Access
All Open Access, Gold, Green
Publisher
Public Library of Science
DOI
10.1371/journal.ppat.1006404
Abstract
When confronted with poor oxygenation, cells adapt by activating survival signaling pathways, including the oxygen-sensitive transcriptional regulators called hypoxia-inducible factor alphas (HIF-αs). We report here that HIF-1α also regulates the life cycle of Epstein-Barr virus (EBV). Incubation of EBV-positive gastric carcinoma AGS-Akata and SNU-719 and Burkitt lymphoma Sal and KemIII cell lines with a prolyl hydroxylase inhibitor, L-mimosine or deferoxamine, or the NEDDylation inhibitor MLN4924 promoted rapid and sustained accumulation of both HIF-1α and lytic EBV antigens. ShRNA knockdown of HIF-1α significantly reduced deferoxamine-mediated lytic reactivation. HIF-1α directly bound the promoter of the EBV primary latent-lytic switch BZLF1 gene, Zp, activating transcription via a consensus hypoxia-response element (HRE) located at nt -83 through -76 relative to the transcription initiation site. HIF-1α did not activate transcription from the other EBV immediate-early gene, BRLF1. Importantly, expression of HIF-1α induced EBV lytic-gene expression in cells harboring wild-type EBV, but not in cells infected with variants containing base-pair substitution mutations within this HRE. Human oral keratinocyte (NOK) and gingival epithelial (hGET) cells induced to differentiate by incubation with either methyl cellulose or growth in organotypic culture accumulated both HIF-1α and Blimp-1α, another cellular factor implicated in lytic reactivation. HIF-1α activity also accumulated along with Blimp-1α during B-cell differentiation into plasma cells. Furthermore, most BZLF1-expressing cells observed in lymphomas induced by EBV in NSG mice with a humanized immune system were located distal to blood vessels in hypoxic regions of the tumors. Thus, we conclude that HIF-1α plays central roles in both EBV’s natural life cycle and EBV-associated tumorigenesis. We propose that drugs that induce HIF-1α protein accumulation are good candidates for development of a lytic-induction therapy for treating some EBV-associated malignancies. © 2017 Kraus et al.
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Knowledge Taxonomy Level 1
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Knowledge Taxonomy Level 3
Funding Sponsor
National Cancer Institute
License
CC BY
Rights
Author
Publication Source
Scopus