Bortezomib induction of C/EBP mediates Epstein-Barr virus lytic activation in Burkitt lymphoma

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Blood (Impact Factor: 10.45). 03/2011; 117(23):6297-303. DOI: 10.1182/blood-2011-01-332379
Source: PubMed


Epstein-Barr virus (EBV) is associated with a variety of lymphoid malignancies. Bortezomib activates EBV lytic gene expression. Bortezomib, a proteasome inhibitor, leads to increased levels of CCAAT/enhancer-binding proteinβ (C/EBPβ) in a variety of tumor cell lines. C/EBPβ activates the promoter of the EBV lytic switch gene ZTA. Bortezomib treatment leads to increased binding of C/EBP to previously recognized binding sites in the ZTA promoter. Knockdown of C/EBPβ inhibits bortezomib activation of EBV lytic gene expression. Bortezomib also induces the unfolded protein response (UPR), as evidenced by increases in ATF4, CHOP10, and XBP1s and cleavage of ATF6. Thapsigargin, an inducer of the UPR that does not interfere with proteasome function, also induces EBV lytic gene expression. The effects of thapsigargin on EBV lytic gene expression are also inhibited by C/EBPβ knock-down. Therefore, C/EBPβ mediates the activation of EBV lytic gene expression associated with bortezomib and another UPR inducer.

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Available from: Meir Shamay, Nov 24, 2015
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    • "It is worth considering in this respect that there is increasing interest in pharmacologic activation of lytic viral expression in EBV-driven malignancies [193]. Several drugs are able to trigger EBV lytic cycle, including gemcitabine, doxorubicin, various histone deacetylase inhibitors (trichostatin A, sodium butyrate, valproic acid, suberoylanilide hydroxamic acid), and bortezomib [193–195]. Particularly promising is the combination of EBV lytic cycle inducers with antiviral agents, as shown by the results of a phase I/II trial of arginine butyrate and gancyclovir in refractory EBV-associated lymphoid malignancies [196]. "
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