Inhibition of Tip60 reduces lytic and latent gene expression of Kaposi's sarcoma-associated herpes virus (KSHV) and proliferation of KSHV-infected tumor cells

Sydney Simpson, Guillaume Fiches, Maxime J. Jean, Michael Dieringer, James McGuinness, Sinu P. John, Meir Shamay, Prashant Desai, Jian Zhu, Netty G. Santoso

Research output: Contribution to journalArticlepeer-review

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus responsible for the development of Kaposi's sarcoma, primary effusion lymphoma (PEL), and Multicentric Castleman's disease in immunocompromised individuals. Despite the burden of these diseases there are few treatment options for afflicted individuals, due in part to our limited understanding of virus-host interactions. Tip60, a histone aceytltransferase (HAT) has been previously shown to interact with both the KSHV latency associated nuclear antigen protein (LANA), which is the main factor in maintaining the viral latent state, and ORF36, a viral kinase expressed in the lytic phase. We further investigated Tip60-virus interaction to ascertain Tip60's role in the viral life cycle and its potential as a target for future therapeutics. Through modulation of Tip60 expression in HEK293T cells harboring a plasmid containing the KSHV viral episome, Bac36, we found that Tip60 is vital for both lytic replication as well as efficient expression of latent genes. Interestingly, Tip60 small molecule inhibitors, MG149 and NU9056, similarly inhibited latent and lytic genes, and reduced virion production in wild-type KSHV+/EBV- PEL, BCBL-1 cells. Long-term treatment with these Tip60 inhibitors selectively decreased the viability of KSHV-infected B lymphoma cells compared to uninfected cells. From this study, we conclude that Tip60 is important for KSHV infection and its associated cancer development, and Tip60 is therefore a potential target for future antiviral and anticancer therapeutics.

Original languageEnglish (US)
Article number788
JournalFrontiers in Microbiology
Volume9
Issue numberAPR
DOIs
StatePublished - Apr 24 2018

Keywords

  • HHV-8
  • KSHV
  • Kaposi's sarcoma
  • MG149
  • NU9056
  • Primary effusion lymphoma
  • Tip60

ASJC Scopus subject areas

  • Microbiology
  • Microbiology (medical)

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