Direct and efficient cellular transformation of primary rat mesenchymal precursor cells by KSHV

Jones, Tiffany; Ye, Fengchun; Bedolla, Roble; Huang, Yufei; Meng, Jia; Qian, Liwu; Pan, Heng; Zhou, Fuchun; Moody, Rosalie; Wagner, Brent; Arar, Mazen Y; Gao, Shou‐Jiang

doi:10.1172/jci58530

Cited by 105 publications

(235 citation statements)

References 29 publications

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“…Supernatants from uninduced BCBL-1 cells or BCBL-1 cells treated with NAM, sirtinol, and NaB for 4 days were collected and filtered through 0.45-m-pore-size filters. The filtered supernatants were then used to infect rat mesenchymal precursor cells (MM cells) to quantify the relative virus titers as previously described (25,26).…”

Section: Methodsmentioning

confidence: 99%

“…KSHV BAC36 contains a green fluorescent protein (GFP) cassette that can be used to track the infection of cells by the virus (16,25). We estimated the relative yields of infectious virions by inoculating MM cells, which are highly susceptible to KSHV infection (26), with supernatants from cells producing infectious virions and subsequently counting the numbers of GFP-positive cells (Fig. 3A).…”

Section: Nam and Sirtinol Increase The Expression Of Kshv Lytic Transmentioning

confidence: 99%

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Activation of Kaposi's Sarcoma-Associated Herpesvirus (KSHV) by Inhibitors of Class III Histone Deacetylases: Identification of Sirtuin 1 as a Regulator of the KSHV Life Cycle

Zhou

et al. 2014

J Virol

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Kaposi's sarcoma-associated herpesvirus (KSHV) establishes persistent latent infection in immunocompetent hosts. Disruption of KSHV latency results in viral lytic replication, which promotes the development of KSHV-related malignancies in immunocompromised individuals. While inhibitors of classes I and II histone deacetylases (HDACs) potently reactivate KSHV from latency, the role of class III HDAC sirtuins (SIRTs) in KSHV latency remains unclear. Here, we examined the effects of inhibitors of SIRTs, nicotinamide (NAM) and sirtinol, on KSHV reactivation from latency. Treatment of latently KSHV-infected cells with NAM or sirtinol induced transcripts and proteins of the master lytic transactivator RTA (ORF50), early lytic genes ORF57 and ORF59, and late lytic gene ORF65 and increased the production of infectious virions. NAM increased the acetylation of histones H3 and H4 as well as the level of the active histone H3 trimethyl Lys4 (H3K4me3) mark but decreased the level of the repressive histone H3 trimethyl Lys27 (H3K27me3) mark in the RTA promoter. Consistent with these results, we detected SIRT1 binding to the RTA promoter. Importantly, knockdown of SIRT1 was sufficient to increase the expression of KSHV lytic genes. Accordingly, the level of the H3K4me3 mark in the RTA promoter was increased following SIRT1 knockdown, while that of the H3K27me3 mark was decreased. Furthermore, SIRT1 interacted with RTA and inhibited RTA transactivation of its own promoter and that of its downstream target, the viral interleukin-6 gene. These results indicate that SIRT1 regulates KSHV latency by inhibiting different stages of viral lytic replication and link the cellular metabolic state with the KSHV life cycle. IMPORTANCEKaposi's sarcoma-associated herpesvirus (KSHV) is the causal agent of several malignancies, including Kaposi's sarcoma, commonly found in immunocompromised patients. While latent infection is required for the development of KSHV-induced malignancies, viral lytic replication also promotes disease progression. However, the mechanism controlling KSHV latent versus lytic replication remains unclear. In this study, we found that class III histone deacetylases (HDACs), also known as SIRTs, whose activities are linked to the cellular metabolic state, mediate KSHV replication. Inhibitors of SIRTs can reactivate KSHV from latency. SIRTs mediate KSHV latency by epigenetically silencing a key KSHV lytic replication activator, RTA. We found that one of the SIRTs, SIRT1, binds to the RTA promoter to mediate KSHV latency. Knockdown of SIRT1 is sufficient to induce epigenetic remodeling and KSHV lytic replication. SIRT1 also interacts with RTA and inhibits RTA's transactivation function, preventing the expression of its downstream genes. Our results indicate that SIRTs regulate KSHV latency by inhibiting different stages of viral lytic replication and link the cellular metabolic state with the KSHV life cycle.

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Section: Methodsmentioning

confidence: 99%

Section: Nam and Sirtinol Increase The Expression Of Kshv Lytic Transmentioning

confidence: 99%

Activation of Kaposi's Sarcoma-Associated Herpesvirus (KSHV) by Inhibitors of Class III Histone Deacetylases: Identification of Sirtuin 1 as a Regulator of the KSHV Life Cycle

Zhou

et al. 2014

J Virol

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“…KSHV provides a growth advantage to infected endothelial cells. The virus consistently immortalizes, but rarely transforms, primary cells in culture (15)(16)(17)(18)(19). It is only under special circumstances and perhaps upon infection of rare progenitor cells with stem cell properties that the interplay between virus and host leads to a fully transformed state.…”

Section: Introductionmentioning

confidence: 99%

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

Dittmer

Damania

2016

Journal of Clinical Investigation

181

152

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“…The recent development of such a system should facilitate the delineation of the mechanism of KSHV-induced oncogenesis and identification of viral and cellular factors that are essential for this process. 2 KSHV encodes over 2 dozen genes that manifest regulatory functions in cell growth, proliferation, and survival. 1 While most of KSHV-regulatory genes are expressed during viral lytic replication, a number of them, including vFLIP (ORF71), vCyclin (ORF72), LANA (ORF73), and a cluster of microRNAs (miRNA), all of which are located at the latent locus of the viral genome, are expressed during the latent phase of KSHV life cycle.…”

Section: Introductionmentioning

confidence: 99%

Viral Cyclin promotes KSHV-induced cellular transformation and tumorigenesis by overriding contact inhibition

et al. 2014

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Direct and efficient cellular transformation of primary rat mesenchymal precursor cells by KSHV

Cited by 105 publications

References 29 publications

Activation of Kaposi's Sarcoma-Associated Herpesvirus (KSHV) by Inhibitors of Class III Histone Deacetylases: Identification of Sirtuin 1 as a Regulator of the KSHV Life Cycle

Activation of Kaposi's Sarcoma-Associated Herpesvirus (KSHV) by Inhibitors of Class III Histone Deacetylases: Identification of Sirtuin 1 as a Regulator of the KSHV Life Cycle

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

Viral Cyclin promotes KSHV-induced cellular transformation and tumorigenesis by overriding contact inhibition

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