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Article: Counteracting survival functions of EBNA3C in Epstein-Barr virus (EBV)-driven lymphoproliferative diseases by combination of SAHA and bortezomib

TitleCounteracting survival functions of EBNA3C in Epstein-Barr virus (EBV)-driven lymphoproliferative diseases by combination of SAHA and bortezomib
Authors
KeywordsBortezomib
EBNA3
Epstein-Barr virus
Lymphoproliferative disease
SAHA
Issue Date2018
PublisherImpact Journals LLC. The Journal's web site is located at http://www.impactjournals.com/oncotarget/index.html
Citation
Oncotarget, 2018, v. 9 n. 38, p. 25101-25114 How to Cite?
AbstractCombination of suberoylanilide hydroxamic acid (SAHA) and bortezomib (SAHA/ bortezomib) was shown to synergistically induce killing of lymphoblastoid cell lines (LCL) and Burkitt lymphoma (BL) of type III or Wp-restricted latency, both of which express EBNA3A, -3B and -3C proteins. We hypothesize that SAHA/bortezomib can counteract the survival functions conferred by the EBNA3 proteins. We tested the effect of SAHA/bortezomib on the survival of BL cell lines containing EBNA3A, -3B or -3C knockout EBV with or without the respective revertant EBNA3 genes. Isobologram analysis showed that SAHA/bortezomib induced significantly greater synergistic killing of EBNA3C-revertant cells when compared with EBNA3C-knockout cells. Such differential response was not observed in either EBNA3A or -3B revertant versus their knockout pairs. Interestingly, EBNA3C-knockout cells showed significant G2/M arrest whilst EBNA3C-revertant cells and LCLs escaped G2/M arrest induced by SAHA/bortezomib and became more susceptible to the induction of apoptosis. In parallel, SAHA/bortezomib induced stronger expression of p21WAF1 but weaker expression of p-cdc25c, an M-phase inducer phosphatase, in EBNA3C-expressing cells when compared with EBNA3C-knockout cells. SAHA/bortezomib also induced greater growth suppression of EBNA3C-expressing xenografts (EBNA3C-revertant and LCL) than that of EBNA3C-knockout xenografts in SCID mice. In conclusion, our data showed that SAHA/bortezomib could synergistically induce killing of BL and LCL through counteracting the survival functions of EBNA3C, providing a strong basis for clinical testing of this drug combination in patients with EBV-associated lymphoproliferative diseases.
Persistent Identifierhttp://hdl.handle.net/10722/264251
ISSN
2015 Impact Factor: 5.008
2015 SCImago Journal Rankings: 2.294

 

DC FieldValueLanguage
dc.contributor.authorHui, KF-
dc.contributor.authorYeung, PL-
dc.contributor.authorTam, KP-
dc.contributor.authorChiang, AKS-
dc.date.accessioned2018-10-22T07:51:57Z-
dc.date.available2018-10-22T07:51:57Z-
dc.date.issued2018-
dc.identifier.citationOncotarget, 2018, v. 9 n. 38, p. 25101-25114-
dc.identifier.issn1949-2553-
dc.identifier.urihttp://hdl.handle.net/10722/264251-
dc.description.abstractCombination of suberoylanilide hydroxamic acid (SAHA) and bortezomib (SAHA/ bortezomib) was shown to synergistically induce killing of lymphoblastoid cell lines (LCL) and Burkitt lymphoma (BL) of type III or Wp-restricted latency, both of which express EBNA3A, -3B and -3C proteins. We hypothesize that SAHA/bortezomib can counteract the survival functions conferred by the EBNA3 proteins. We tested the effect of SAHA/bortezomib on the survival of BL cell lines containing EBNA3A, -3B or -3C knockout EBV with or without the respective revertant EBNA3 genes. Isobologram analysis showed that SAHA/bortezomib induced significantly greater synergistic killing of EBNA3C-revertant cells when compared with EBNA3C-knockout cells. Such differential response was not observed in either EBNA3A or -3B revertant versus their knockout pairs. Interestingly, EBNA3C-knockout cells showed significant G2/M arrest whilst EBNA3C-revertant cells and LCLs escaped G2/M arrest induced by SAHA/bortezomib and became more susceptible to the induction of apoptosis. In parallel, SAHA/bortezomib induced stronger expression of p21WAF1 but weaker expression of p-cdc25c, an M-phase inducer phosphatase, in EBNA3C-expressing cells when compared with EBNA3C-knockout cells. SAHA/bortezomib also induced greater growth suppression of EBNA3C-expressing xenografts (EBNA3C-revertant and LCL) than that of EBNA3C-knockout xenografts in SCID mice. In conclusion, our data showed that SAHA/bortezomib could synergistically induce killing of BL and LCL through counteracting the survival functions of EBNA3C, providing a strong basis for clinical testing of this drug combination in patients with EBV-associated lymphoproliferative diseases.-
dc.languageeng-
dc.publisherImpact Journals LLC. The Journal's web site is located at http://www.impactjournals.com/oncotarget/index.html-
dc.relation.ispartofOncotarget-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectBortezomib-
dc.subjectEBNA3-
dc.subjectEpstein-Barr virus-
dc.subjectLymphoproliferative disease-
dc.subjectSAHA-
dc.titleCounteracting survival functions of EBNA3C in Epstein-Barr virus (EBV)-driven lymphoproliferative diseases by combination of SAHA and bortezomib-
dc.typeArticle-
dc.identifier.emailHui, KF: kfhui@hku.hk-
dc.identifier.emailChiang, AKS: chiangak@hku.hk-
dc.identifier.authorityChiang, AKS=rp00403-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.18632/oncotarget.25341-
dc.identifier.scopuseid_2-s2.0-85047185832-
dc.identifier.hkuros295010-
dc.identifier.volume9-
dc.identifier.issue38-
dc.identifier.spage25101-
dc.identifier.epage25114-
dc.publisher.placeUnited States-

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