Cancer Angiogenesis Induced by Kaposi Sarcoma–Associated Herpesvirus Is Mediated by EZH2

He, Maoxia; Zhang, Wei; Bakken, Thomas; Schutten, Melissa M.; Tóth, Zsolt; Jung, Jae U.; Gill, Parkash S.; Cannon, Mark; Gao, Shou‐Jiang

doi:10.1158/0008-5472.can-11-2876

Cited by 70 publications

(60 citation statements)

References 50 publications

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“…This assumption is consistent with previously published observation that several genes associated with immune modulation were suppressed (6). Also, it was recently demonstrated that EZH2 plays a role in KSHV cancer angiogenesis (16). Hence, we wanted to test the possibility that PAN RNA interacts with protein components comprising the PRC2.…”

Section: Fig 4 Pan Rna Is Expressed In Uninduced Bcbl-1 Cells Rna Wamentioning

confidence: 99%

Regulation of Viral and Cellular Gene Expression by Kaposi's Sarcoma-Associated Herpesvirus Polyadenylated Nuclear RNA

Rossetto

Tarrant-Elorza

Verma

et al. 2013

J Virol

116

195

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Kaposi's sarcoma-associated herpesvirus (KSHV) is the cause of Kaposi's sarcoma and body cavity lymphoma. In cell culture, KSHV results in a latent infection, and lytic reactivation is usually induced with the expression of K-Rta or by treatment with phorbol 12-myristate 13-acetate (TPA) and/or n-butyrate. Lytic infection is marked by the activation of the entire viral genomic transcription cascade and the production of infectious virus. KSHV-infected cells express a highly abundant, long, noncoding transcript referred to as polyadenylated nuclear RNA (PAN RNA). PAN RNA interacts with specific demethylases and physically binds to the KSHV genome to mediate activation of viral gene expression. A recombinant BACmid lacking the PAN RNA locus fails to express K-Rta and does not produce virus. We now show that the lack of PAN RNA expression results in the failure of the initiation of the entire KSHV transcription program. In addition to previous findings of an interaction with demethylases, we show that PAN RNA binds to protein components of Polycomb repression complex 2 (PRC2). RNA-Seq analysis using cell lines that express PAN RNA shows that transcription involving the expression of proteins involved in cell cycle, immune response, and inflammation is dysregulated. Expression of PAN RNA in various cell types results in an enhanced growth phenotype, higher cell densities, and increased survival compared to control cells. Also, PAN RNA expression mediates a decrease in the production of inflammatory cytokines. These data support a role for PAN RNA as a major global regulator of viral and cellular gene expression.K aposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic gamma herpesvirus that is the cause of Kaposi's sarcoma (1, 2). KSHV infection in cell culture manifests mainly as a latent infection; however, there is a percentage of spontaneous lytic reactivation. Lytic infection is marked by the production of infectious virus, whereas latency is characterized by the lack of infectious virus production and the expression of a limited number of viral transcripts and proteins. One of the most abundant transcripts present in KSHV-infected cells is a long noncoding RNA, referred to as polyadenylated nuclear RNA (PAN RNA) (3, 4).We previously showed that PAN RNA interacts with cell-and virus-encoded factors and mediates the regulation of immune response gene expression (5, 6). Data from our laboratory and others indicated that PAN RNA is a major regulator of viral gene expression through a mechanism that involves a direct interaction with the viral chromosome (5, 7). PAN RNA interacts with the demethylases UTX and JMJD3 to remove the suppressive H3K23me3 mark within the KSHV viral genome. In a recent study describing the transcriptome of KSHV-infected cell lines, PAN RNA was detected in the absence of lytic-phase induction, suggesting that PAN RNA is expressed during chronic latent infection in cell culture (8). This observation suggests that PAN RNA has the potential to influence viral and cellular gene expressio...

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Section: Fig 4 Pan Rna Is Expressed In Uninduced Bcbl-1 Cells Rna Wamentioning

confidence: 99%

Regulation of Viral and Cellular Gene Expression by Kaposi's Sarcoma-Associated Herpesvirus Polyadenylated Nuclear RNA

Rossetto

Tarrant-Elorza

Verma

et al. 2013

J Virol

116

195

View full text Add to dashboard Cite

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“…Hey1, a downstream effector of the Notch pathway, which plays a critical role in embryonic vascular development, was a candidate for elucidating the role of the Notch signaling pathway in Kaposi sarcoma angiogenesis (25,26). Moreover, the mediation of Hey1 by multiple KSHV components indicates its significance to clinical treatment of Kaposi sarcoma (8,12,15,18,42). However, these studies have generally delineated the involvement of Notch signaling, including Hey1, during KSHV infection, but have omitted functional study of Hey1 in Kaposi sarcoma.…”

Section: Discussionmentioning

confidence: 99%

“…Multiple KSHV-encoded viral proteins have been demonstrated to activate the Notch pathway (3,6,12,(16)(17)(18)(38)(39)(40). We reported previously that KSHV LANA stabilizes ICN and contributes to cell proliferation (30).…”

Section: Lana Was the Major Component That Upregulated Hey1 Expressiomentioning

confidence: 98%

“…Moreover, the KSHV genome itself encodes viral cytokine-and chemokine-like factors that can activate endothelial cells and stimulate angiogenesis (4,(8)(9)(10)(11)(12). However, although it is a welldefined angiogenesis-associated pathway, whether the Notch signaling pathway can be manipulated by KSHV in Kaposi sarcoma angiogenesis, is largely unknown (13,14).…”

Section: Introductionmentioning

confidence: 99%

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Latency-Associated Nuclear Antigen of Kaposi Sarcoma–Associated Herpesvirus Promotes Angiogenesis through Targeting Notch Signaling Effector Hey1

Wang

Tian

et al. 2014

Cancer Research

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Notch signaling has been implicated in the pathogenesis of Kaposi sarcoma. Kaposi sarcoma is an angioproliferative neoplasm that originates from Kaposi sarcoma-associated herpesvirus (KSHV) infection. Previously, we showed that the KSHV LANA protein can stabilize intracellular Notch in KSHV-infected tumor cells and promote cell proliferation. However, whether Notch signaling functions in pathologic angiogenesis of Kaposi sarcoma remains largely unknown. Hey1, an essential downstream effector of the Notch signaling pathway, has been demonstrated to play a fundamental role in vascular development. In the present study, we performed whole transcriptome, paired-end sequencing on three patient-matched clinical Kaposi sarcoma specimens and their corresponding adjacent stroma samples, with an average depth of 42 million reads per sample. Dll4, Hey1, and HeyL displayed significant upregulation in Kaposi sarcoma. Further verification based on immunohistochemistry analysis demonstrated that Hey1 was indeed highly expressed in Kaposi sarcoma lesions. Using the Matrigel plug assay, we showed that downregulation of Hey1 and g-secretase inhibitor treatment caused dramatic reduction in the formation of new blood vessels in mice. Interestingly, LANA was responsible for the elevated level of Hey1 through inhibition of its degradation. Importantly, Hey1 stabilized by LANA promoted the neoplastic vasculature. Taken together, our data suggest that hijacking of the proangiogenic property of Hey1 by LANA is an important strategy utilized by KSHV to achieve pathologic angiogenesis and that Hey1 is a potential therapeutic target in Kaposi sarcoma. Cancer Res; 74(7); 2026-37. Ó2014 AACR.

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“…Knockdown with shRNAs was performed as previously described (49). Briefly, HUVEC were infected with shRNA-carrying lentiviruses in the presence of 10 g/ml Polybrene (Sigma-Aldrich).…”

Section: Antibodies and Reagentsmentioning

confidence: 99%

Screening of the Human Kinome Identifies MSK1/2-CREB1 as an Essential Pathway Mediating Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication during Primary Infection

Cheng

Sawant

Lan

et al. 2015

J Virol

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Viruses often hijack cellular pathways to facilitate infection and replication. Kaposi's sarcoma-associated herpesvirus (KSHV) is IMPORTANCEKaposi's sarcoma-associated herpesvirus (KSHV) is a human tumor virus associated with several cancers. Through genome-wide kinase screening, we found that KSHV activates the MSK1/2-CREB1 pathway during primary infection and that it depends on this pathway for viral lytic replication. Inhibition of this pathway blocks KSHV lytic replication. These results illustrate a mechanism by which KSHV hijacks a cellular pathway for its replication, and they identify a potential therapeutic target. V iruses depend on cell signaling pathways for successful infection and replication. Identification of pathways hijacked by viruses not only reveals the mechanisms of infection and replication of these viruses but also provides novel therapeutic targets. Kaposi's sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus etiologically associated with Kaposi's sarcoma (KS), a vascular tumor of endothelial cells commonly found in AIDS patients, and with two B-cell lymphoproliferative diseases, namely, primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD) (1-3). The early phase of primary KSHV infection is a highly regulated multistep event consisting of virion attachment and binding, membrane fusion, internalization, intracellular trafficking, and early viral gene expression (4). KSHV infection induces phosphorylation of cellular proteins, leading to the activation of signal transduction pathways. A number of these pathways regulate KSHV entry, trafficking, and viral gene expression (4). Binding of KSHV glycoproteins to cellular receptors activates focal adhesion kinase (FAK), Src, phosphatidylinositol-3-kinases (PI3Ks), and mitogen-activated protein kinases (MAPKs), including MEK/extracellular signal-regulated kinase (MEK/ERK), p38, and Jun N-terminal kinase (JNK), facilitating KSHV internalization and trafficking (5-10). This process depends on rearrangements of the actin and microtubule cytoskeletons and on factors, such as Rho-GTPases and diaphanous-2 (Dia-2), that regulate their dynamics (8, 11). KSHV entry and trafficking rely on the dynamics of the ubiquitin/proteasome system and on activation of the E3 ligase c-Cbl to maintain the endosomal activities and cellular signaling (12, 13).Successful KSHV infection requires the coordinated expres-

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Cancer Angiogenesis Induced by Kaposi Sarcoma–Associated Herpesvirus Is Mediated by EZH2

Cited by 70 publications

References 50 publications

Regulation of Viral and Cellular Gene Expression by Kaposi's Sarcoma-Associated Herpesvirus Polyadenylated Nuclear RNA

Regulation of Viral and Cellular Gene Expression by Kaposi's Sarcoma-Associated Herpesvirus Polyadenylated Nuclear RNA

Latency-Associated Nuclear Antigen of Kaposi Sarcoma–Associated Herpesvirus Promotes Angiogenesis through Targeting Notch Signaling Effector Hey1

Screening of the Human Kinome Identifies MSK1/2-CREB1 as an Essential Pathway Mediating Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication during Primary Infection

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