1. Reactivation of Epstein-Barr Virus by HIF-1α Requires p53.
- Author
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Kraus, Richard J., Cordes, Blue-leaf A., Sathiamoorthi, Saraniya, Patel, Parita, Xueying Yuan, Iempridee, Tawin, Xianming Yu, Lee, Denis L., Lambert, Paul F., and Mertz, Janet E.
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EPSTEIN-Barr virus , *VIRUS reactivation , *P53 protein , *IRON chelates , *ATAXIA telangiectasia , *CELL lines , *P53 antioncogene - Abstract
We previously reported that the cellular transcription factor hypoxiainducible factor 1+ (HIF-1+) binds a hypoxia response element (HRE) located within the promoter of Epstein-Barr virus's (EBV's) latent-lytic switch BZLF1 gene, Zp, inducing viral reactivation. In this study, EBV-infected cell lines derived from gastric cancers and Burkitt lymphomas were incubated with HIF-1+-stabilizing drugs: the iron chelator deferoxamine (Desferal [DFO]), a neddylation inhibitor (pevonedistat [MLN- 4924]), and a prolyl hydroxylase inhibitor (roxadustat [FG-4592]). DFO and MLN-4924, but not FG-4592, induced accumulation of both lytic EBV proteins and phosphorylated p53 in cell lines that contain a wild-type p53 gene. FG-4592 also failed to activate transcription from Zp in a reporter assay despite inducing accumulation of HIF-1+ and transcription from another HRE-containing promoter. Unexpectedly, DFO failed to induce EBV reactivation in cell lines that express mutant or no p53 or when p53 expression was knocked down with short hairpin RNAs (shRNAs). Likewise, HIF-1+ failed to activate transcription from Zp when p53 was knocked out by CRISPR-Cas9. Importantly, DFO induced binding of p53 as well as HIF-1+ to Zp in chromatin immunoprecipitation (ChIP) assays, but only when the HRE was present. Nutlin-3, a drug known to induce accumulation of phosphorylated p53, synergized with DFO and MLN-4924 in inducing EBV reactivation. Conversely, KU-55933, a drug that inhibits ataxia telangiectasia mutated, thereby preventing p53 phosphorylation, inhibited DFO-induced EBV reactivation. Lastly, activation of Zp transcription by DFO and MLN-4924 mapped to its HRE. Thus, we conclude that induction of BZLF1 gene expression by HIF-1+ requires phosphorylated, wild-type p53 as a coactivator, with HIF-1+ binding recruiting p53 to Zp. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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