TY - JOUR
T1 - Inhibition of Tip60 reduces lytic and latent gene expression of Kaposi's sarcoma-associated herpes virus (KSHV) and proliferation of KSHV-infected tumor cells
AU - Simpson, Sydney
AU - Fiches, Guillaume
AU - Jean, Maxime J.
AU - Dieringer, Michael
AU - McGuinness, James
AU - John, Sinu P.
AU - Shamay, Meir
AU - Desai, Prashant
AU - Zhu, Jian
AU - Santoso, Netty G.
N1 - Funding Information:
We would like to thank Dr. Edward Berger at NIH and Dr. Shou-Jiang Gao at the USC for providing the MC116.219 cells and the Bac36 plasmid, respectively. The following reagent was obtained through the NIH AIDS Reagent Program: BCBL-1 from Drs. Michael McGrath and Don Ganem. This work was supported by grants from NIH (R01DE025447 and R33AI116180) to JZ. Additionally, SS was supported by the HIV Pathogenesis and Replication Training Grant (T32AI049815) and MJ was supported by the Pre-and Post-doctoral Training Program in Immunology institutional grant from NIH (T32A1007285).
Publisher Copyright:
© 2018 Simpson, Fiches, Jean, Dieringer, McGuinness, John, Shamay, Desai, Zhu and Santoso.
PY - 2018/4/24
Y1 - 2018/4/24
N2 - 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.
AB - 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.
KW - HHV-8
KW - KSHV
KW - Kaposi's sarcoma
KW - MG149
KW - NU9056
KW - Primary effusion lymphoma
KW - Tip60
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U2 - 10.3389/fmicb.2018.00788
DO - 10.3389/fmicb.2018.00788
M3 - Article
C2 - 29740418
AN - SCOPUS:85045915462
SN - 1664-302X
VL - 9
JO - Frontiers in Microbiology
JF - Frontiers in Microbiology
IS - APR
M1 - 788
ER -