Valproic Acid Antagonizes the Capacity of Other Histone Deacetylase Inhibitors To Activate the Epstein-Barr Virus Lytic Cycle

Daigle, Derek; Gradoville, Lyndle; Tuck, David; Schulz, Vincent P.; Wang’ondu, Ruth; Ye, Jianjiang; Gorres, Kelly; Miller, George

doi:10.1128/jvi.02659-10

Cited by 43 publications

(65 citation statements)

References 102 publications

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“…In fact, VPA blocks viral lytic reactivation by butyrate and by all other inducing stimuli, including azacytidine, anti-IgG in Akata cells, and TPA in Raji cells (29). MS-275 and apicidin, representing two additional classes of HDAC inhibitors, and suberoylanilide hydroxamic acid (SAHA) reactivated EBV in HH514-16 cells; this activity was also inhibited by VPA (29). Conversely, VPA is a strong inducer of the lytic cycle of KSHV (29)(30)(31).…”

Section: Importancementioning

confidence: 99%

“…1), a branchedchain SCFA and an HDAC inhibitor, does not induce the EBV lytic cycle, even though treatment with VPA results in hyperacetylated histones (28). In fact, VPA blocks viral lytic reactivation by butyrate and by all other inducing stimuli, including azacytidine, anti-IgG in Akata cells, and TPA in Raji cells (29). MS-275 and apicidin, representing two additional classes of HDAC inhibitors, and suberoylanilide hydroxamic acid (SAHA) reactivated EBV in HH514-16 cells; this activity was also inhibited by VPA (29).…”

Section: Importancementioning

confidence: 99%

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Activation and Repression of Epstein-Barr Virus and Kaposi's Sarcoma-Associated Herpesvirus Lytic Cycles by Short- and Medium-Chain Fatty Acids

Gorres

Daigle

Mohanram

et al. 2014

J Virol

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The lytic cycles of Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are induced in cell culture by sodium butyrate (NaB), a short-chain fatty acid (SCFA) histone deacetylase (HDAC) inhibitor. Valproic acid (VPA), another SCFA and an HDAC inhibitor, induces the lytic cycle of KSHV but blocks EBV lytic reactivation. To explore the hypothesis that structural differences between NaB and VPA account for their functional effects on the two related viruses, we investigated the capacity of 16 structurally related short-and medium-chain fatty acids to promote or prevent lytic cycle reactivation. SCFAs differentially affected EBV and KSHV reactivation. KSHV was reactivated by all SCFAs that are HDAC inhibitors, including phenylbutyrate. However, several fatty acid HDAC inhibitors, such as isobutyrate and phenylbutyrate, did not reactivate EBV. Reactivation of KSHV lytic transcripts could not be blocked completely by any fatty acid tested. In contrast, several medium-chain fatty acids inhibited lytic activation of EBV. Fatty acids that blocked EBV reactivation were more lipophilic than those that activated EBV. VPA blocked activation of the BZLF1 promoter by NaB but did not block the transcriptional function of ZEBRA. VPA also blocked activation of the DNA damage response that accompanies EBV lytic cycle activation. Properties of SCFAs in addition to their effects on chromatin are likely to explain activation or repression of EBV. We concluded that fatty acids stimulate the two related human gammaherpesviruses to enter the lytic cycle through different pathways. IMPORTANCELytic reactivation of EBV and KSHV is needed for persistence of these viruses and plays a role in carcinogenesis. Our direct comparison highlights the mechanistic differences in lytic reactivation between related human oncogenic gammaherpesviruses. Our findings have therapeutic implications, as fatty acids are found in the diet and produced by the human microbiota. Small-molecule inducers of the lytic cycle are desired for oncolytic therapy. Inhibition of viral reactivation, alternatively, may prove useful in cancer treatment. Overall, our findings contribute to the understanding of pathways that control the latent-to-lytic switch and identify naturally occurring molecules that may regulate this process.

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Section: Importancementioning

confidence: 99%

Section: Importancementioning

confidence: 99%

Activation and Repression of Epstein-Barr Virus and Kaposi's Sarcoma-Associated Herpesvirus Lytic Cycles by Short- and Medium-Chain Fatty Acids

Gorres

Daigle

Mohanram

et al. 2014

J Virol

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“…The potential contribution of differential histone modifications, particularly acetylation of histones H3 and H4 to the regulation of EBV lytic cycle has been addressed, providing support for opening up of the chromatin environment during the lytic cycle (6, 7, 22-24, 32, 51). However, Countryman et al discovered that this model is too simplistic to account for the silencing of lytic promoters during latency by demonstrating that reprogramming histone acetylation is not sufficient to activate the EBV lytic cycle in all cell types (7,8).…”

mentioning

confidence: 99%

Dynamic Chromatin Environment of Key Lytic Cycle Regulatory Regions of the Epstein-Barr Virus Genome

Ramasubramanyan

Osborn

Flower

et al. 2012

J Virol

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The ability of Epstein-Barr virus (EBV) to establish latency allows it to evade the immune system and to persist for the lifetime of its host; one distinguishing characteristic is the lack of transcription of the majority of viral genes. Entry into the lytic cycle is coordinated by the viral transcription factor, Zta (BZLF1, ZEBRA, and EB1), and downstream effectors, while viral genome replication requires the concerted action of Zta and six other viral proteins at the origins of lytic replication. We explored the chromatin context at key EBV lytic cycle promoters (BZLF1, BRLF1, BMRF1, and BALF5) and the origins of lytic replication during latency and lytic replication. We show that a repressive heterochromatin-like environment (trimethylation of histone H3 at lysine 9 [H3K9me3] and lysine 27 [H3K27me3]), which blocks the interaction of some transcription factors with DNA, encompasses the key early lytic regulatory regions. Epigenetic silencing of the EBV genome is also imposed by DNA methylation during latency. The chromatin environment changes during the lytic cycle with activation of histones H3, H4, and H2AX occurring at both the origins of replication and at the key lytic regulatory elements. We propose that Zta is able to reverse the effects of latency-associated repressive chromatin at EBV early lytic promoters by interacting with Zta response elements within the H3K9me3-associated chromatin and demonstrate that these interactions occur in vivo. Since the interaction of Zta with DNA is not inhibited by DNA methylation, it is clear that Zta uses two routes to overcome epigenetic silencing of its genome.

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“…44 SAHA was, however, able to induce EBV lytic cycle in HH514-16 BL, P3HR1, and Daudi cells. 45 It must be noted that SAHA has not been studied in all types of cancers; further studies are needed to elucidate the effectiveness of SAHA in various cancers.…”

Section: Ebv-related Infectionsmentioning

confidence: 99%

Epstein-Barr Virus (EBV) and the Effectiveness of Suberoylanilide Hydroxamic Acid (SAHA) as a Treatment for EBV Infection and Associated Cancers

Bart¹,

Johnson²,

DeGol³

et al. 2013

Advances in Tumor Virology

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Since being discovered in 1964, Epstein-Barr virus (EBV) has become a growing concern. Clinically, EBV is responsible for many diseases, most notably infectious mononucleosis. In addition to mononucleosis, EBV causes several cancers such as Hodgkin's lymphoma, Burkitt's lymphoma, and nasopharyngeal carcinoma (NPC). Suberoylanilide hydroxamic acid (SAHA) is an anti-cancer drug that inhibits growth and proliferation of various EBV-related cancers. SAHA acts as a histone deacetylase (HDAC) inhibitor. The responsiveness of SAHA treatment stems from the induction of EBV's lytic cycle.

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Valproic Acid Antagonizes the Capacity of Other Histone Deacetylase Inhibitors To Activate the Epstein-Barr Virus Lytic Cycle

Cited by 43 publications

References 102 publications

Activation and Repression of Epstein-Barr Virus and Kaposi's Sarcoma-Associated Herpesvirus Lytic Cycles by Short- and Medium-Chain Fatty Acids

Activation and Repression of Epstein-Barr Virus and Kaposi's Sarcoma-Associated Herpesvirus Lytic Cycles by Short- and Medium-Chain Fatty Acids

Dynamic Chromatin Environment of Key Lytic Cycle Regulatory Regions of the Epstein-Barr Virus Genome

Epstein-Barr Virus (EBV) and the Effectiveness of Suberoylanilide Hydroxamic Acid (SAHA) as a Treatment for EBV Infection and Associated Cancers

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