Inhibition of class I histone deacetylases by romidepsin potently induces Epstein‐Barr virus lytic cycle and mediates enhanced cell death with ganciclovir. Issue 1 (11th August 2015)

• Record Type: Journal Article
• Authors: Hui, Kwai Fung; Cheung, Arthur Kwok Leung; Choi, Chung King; Yeung, Po Ling; Middeldorp, Jaap M.; Lung, Maria Li; Tsao, Sai Wah; Chiang, Alan Kwok Shing
• Is Part Of: International journal of cancer. Volume 138:Issue 1(2016:Jan. 01)
• Page Start: 125
• Page End: 136
• Publication Date: 2015-08-11
• Subjects: Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.29698
• Languages: English
• ISSNs: 0020-7136

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 <italic>in vitro</italic> 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 <italic>in vitro</italic> and <italic>in vivo</italic>. 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 (<italic>versus</italic> ∼800 nM achievable concentration in patients' plasma) in more than 75% of cells. Upregulation of p21<sup>WAF1</sup>, which is negatively regulated by class I HDACs, was observed before the induction of EBV lytic cycle. The upregulation of p21<sup>WAF1</sup> 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.</p> </abstract>