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Article: Inhibition of class I histone deacetylases by romidepsin potently induces Epstein-Barr virus lytic cycle and mediates enhanced cell death with ganciclovir

TitleInhibition of class I histone deacetylases by romidepsin potently induces Epstein-Barr virus lytic cycle and mediates enhanced cell death with ganciclovir
Authors
Issue Date2016
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www3.interscience.wiley.com/journal/29331/home
Citation
International Journal of Cancer, 2016, v. 138 n. 1, p. 125–136 How to Cite?
AbstractPan-histone deacetylase (HDAC) inhibitors, which inhibit 11 HDAC isoforms, are widely used to induce Epstein-Barr virus (EBV) lytic cycle in EBV-associated cancers in vitro and in clinical trials. Here, we hypothesized that inhibition of one or several specific HDAC isoforms by selective HDAC inhibitors could potently induce EBV lytic cycle in EBV-associated malignancies such as nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC). We found that inhibition of class I HDACs, particularly HDAC-1, -2 and -3, was sufficient to induce EBV lytic cycle in NPC and GC cells in vitro and in vivo. Among a panel of selective HDAC inhibitors, the FDA-approved HDAC inhibitor romidepsin was found to be the most potent lytic inducer, which could activate EBV lytic cycle at ∼0.5 to 5 nM (versus ∼800 nM achievable concentration in patients' plasma) in more than 75% of cells. Upregulation of p21WAF1 , which is negatively regulated by class I HDACs, was observed before the induction of EBV lytic cycle. The upregulation of p21WAF1 and induction of lytic cycle were abrogated by a specific inhibitor of PKC-δ but not the inhibitors of PI3K, MEK, p38 MAPK, JNK or ATM pathways. Interestingly, inhibition of HDAC-1, -2 and -3 by romidepsin or shRNA knockdown could confer susceptibility of EBV-positive epithelial cells to the treatment with ganciclovir (GCV). In conclusion, we demonstrated that inhibition of class I HDACs by romidepsin could potently induce EBV lytic cycle and mediate enhanced cell death with GCV, suggesting potential application of romidepsin for the treatment of EBV-associated cancers.
Persistent Identifierhttp://hdl.handle.net/10722/216730
ISSN
2015 Impact Factor: 5.531
2015 SCImago Journal Rankings: 2.657
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHui, KF-
dc.contributor.authorCheung, AKL-
dc.contributor.authorChoi, CK-
dc.contributor.authorYeung, PL-
dc.contributor.authorMiddeldorp, JM-
dc.contributor.authorLung, ML-
dc.contributor.authorTsao, GSW-
dc.contributor.authorChiang, AKS-
dc.date.accessioned2015-09-18T05:36:52Z-
dc.date.available2015-09-18T05:36:52Z-
dc.date.issued2016-
dc.identifier.citationInternational Journal of Cancer, 2016, v. 138 n. 1, p. 125–136-
dc.identifier.issn0020-7136-
dc.identifier.urihttp://hdl.handle.net/10722/216730-
dc.description.abstractPan-histone deacetylase (HDAC) inhibitors, which inhibit 11 HDAC isoforms, are widely used to induce Epstein-Barr virus (EBV) lytic cycle in EBV-associated cancers in vitro and in clinical trials. Here, we hypothesized that inhibition of one or several specific HDAC isoforms by selective HDAC inhibitors could potently induce EBV lytic cycle in EBV-associated malignancies such as nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC). We found that inhibition of class I HDACs, particularly HDAC-1, -2 and -3, was sufficient to induce EBV lytic cycle in NPC and GC cells in vitro and in vivo. Among a panel of selective HDAC inhibitors, the FDA-approved HDAC inhibitor romidepsin was found to be the most potent lytic inducer, which could activate EBV lytic cycle at ∼0.5 to 5 nM (versus ∼800 nM achievable concentration in patients' plasma) in more than 75% of cells. Upregulation of p21WAF1 , which is negatively regulated by class I HDACs, was observed before the induction of EBV lytic cycle. The upregulation of p21WAF1 and induction of lytic cycle were abrogated by a specific inhibitor of PKC-δ but not the inhibitors of PI3K, MEK, p38 MAPK, JNK or ATM pathways. Interestingly, inhibition of HDAC-1, -2 and -3 by romidepsin or shRNA knockdown could confer susceptibility of EBV-positive epithelial cells to the treatment with ganciclovir (GCV). In conclusion, we demonstrated that inhibition of class I HDACs by romidepsin could potently induce EBV lytic cycle and mediate enhanced cell death with GCV, suggesting potential application of romidepsin for the treatment of EBV-associated cancers.-
dc.languageeng-
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www3.interscience.wiley.com/journal/29331/home-
dc.relation.ispartofInternational Journal of Cancer-
dc.rightsInternational Journal of Cancer. Copyright © John Wiley & Sons, Inc.-
dc.rightsThis is the peer reviewed version of the following article: International Journal of Cancer, 2016, v. 138 n. 1, p. 125–136, which has been published in final form at http://onlinelibrary.wiley.com/wol1/doi/10.1002/ijc.29698/abstract. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.titleInhibition of class I histone deacetylases by romidepsin potently induces Epstein-Barr virus lytic cycle and mediates enhanced cell death with ganciclovir-
dc.typeArticle-
dc.identifier.emailHui, KF: kfhui@hku.hk-
dc.identifier.emailCheung, AKL: arthurhk@hku.hk-
dc.identifier.emailLung, ML: mlilung@hku.hk-
dc.identifier.emailTsao, GSW: gswtsao@hku.hk-
dc.identifier.emailChiang, AKS: chiangak@hku.hk-
dc.identifier.authorityCheung, AKL=rp01769-
dc.identifier.authorityLung, ML=rp00300-
dc.identifier.authorityTsao, GSW=rp00399-
dc.identifier.authorityChiang, AKS=rp00403-
dc.description.naturepostprint-
dc.identifier.doi10.1002/ijc.29698-
dc.identifier.pmid26205347-
dc.identifier.scopuseid_2-s2.0-84944278920-
dc.identifier.hkuros253253-
dc.identifier.volume138-
dc.identifier.issue1-
dc.identifier.spage125-
dc.identifier.epage136-
dc.identifier.isiWOS:000363203600017-
dc.publisher.placeUnited States-

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