title: Inhibition of class I histone deacetylases by romidepsin potently induces Epstein-Barr virus lytic cycle and mediates enhanced cell death with ganciclovir.
abstract: Pan-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 p21(WAF1) , which is negatively regulated by class I HDACs, was observed before the induction of EBV lytic cycle. The upregulation of p21(WAF1) 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.
authors.affiliation: Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China.
authors.forename: Kwai Fung
authors.initials: KF
authors.lastname: Hui
authors.affiliation: Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China.
authors.forename: Arthur Kwok Leung
authors.initials: AK
authors.lastname: Cheung
authors.affiliation: Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China.
authors.forename: Chung King
authors.initials: CK
authors.lastname: Choi
authors.affiliation: Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China.
authors.forename: Po Ling
authors.initials: PL
authors.lastname: Yeung
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Jaap M
authors.initials: JM
authors.lastname: Middeldorp
authors.affiliation: Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China.|Center for Nasopharyngeal Carcinoma Research, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Maria Li
authors.initials: ML
authors.lastname: Lung
authors.affiliation: Center for Nasopharyngeal Carcinoma Research, The University of Hong Kong, Hong Kong SAR, China.|Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Sai Wah
authors.initials: SW
authors.lastname: Tsao
authors.affiliation: Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China.|Center for Nasopharyngeal Carcinoma Research, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Alan Kwok Shing
authors.initials: AK
authors.lastname: Chiang
mesh_terms: D000107:Acetylation; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D002277:Carcinoma; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D047630:Depsipeptides / Q000494:pharmacology*; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D015774:Ganciclovir / Q000494:pharmacology*; D004854:Herpesvirus 4, Human / Q000187:drug effects* / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000821:virology; D051745:Protein Kinase C-delta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000821:virology; D014775:Virus Activation / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000998:Antiviral Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D006657:Histones; C087123:romidepsin; D064007:Ataxia Telangiectasia Mutated Proteins; D051745:Protein Kinase C-delta; D006655:Histone Deacetylases; D015774:Ganciclovir
keywords: Epstein-Barr virus; epithelial cancer; histone deacetylase inhibitor; lytic cycle; romidepsin