Reactivation of Epstein-Barr virus lytic cycle by histone deacetylase inhibitors

Abstract

Epstein-Barr virus (EBV) is closely associated with certain lymphoid and epithelial malignancies such as Burkitt lymphoma, nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC). In the tumor cells, the virus persists in a tight latency, expressing a limited number of latent proteins. Reactivation of EBV lytic cycle from latency leads to expression of many more viral lytic proteins which may provide potential therapeutic targets for the EBV-associated cancers. Histone deacetylase (HDAC) inhibitors belong to an emerging class of anti-cancer agents which work through acetylation of different histone and non-histone proteins in cancer cells. Our previous work showed that various pan-HDAC inhibitors, which inhibit eleven HDAC isoforms, can preferentially reactivate EBV lytic cycle in EBV-positive epithelial rather than lymphoid cancers and mediate enhanced killing of EBV-positive NPC and GC cells through augmentation of apoptotic cell death. Recently, we found that a selective class I HDAC inhibitor, romidepsin, can potently induce EBV lytic cycle in NPC and GC cells and confer susceptibility of the induced cells to killing by an anti-viral agent, ganciclovir, in vitro and in vivo. The reactivation of EBV lytic cycle by romidepsin is related to the inhibition of HDAC-1, -2 and -3 isoforms and the activation of PKC-. Interestingly, our current findings suggest that acetylation of non-histone proteins might also play a role in the regulation of EBV lytic cycle upon HDAC inhibition. In this review, we discuss our recent findings on the mechanisms of EBV lytic cycle reactivation and propose possible strategies in using HDAC inhibitors for the treatment of EBV-associated cancers.