Methylation status and AP1 elements are involved in EBV-mediated miR-155 expression in EBV positive lymphoma cells

Yin, Qinyan; Wang, Xia; Roberts, Claire; Flemington, Erik K.; Lasky, Joseph A.

doi:10.1016/j.virol.2016.04.005

Cited by 19 publications

(10 citation statements)

References 50 publications

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“…Thus, both NF-κB and p38 are required for regulation of miR-155 by LMP1 in our chimeric, inducible system. This is consistent with previous reports (Gatto et al, 2008;Rahadiani et al, 2008;Yin et al, 2008Yin et al, , 2016, validating our experimental approach. Notably, miR-155 upregulation was significantly reduced by GDC-0941, a PI3K p110α,δ dual-specific inhibitor, and BYL719, a PI3K p110α-specific inhibitor, but not CAL-101, a PI3K p110δ-specific inhibitor ( Figure 3A).…”

supporting

confidence: 94%

“…Collectively, our data and that of Wang et al suggest additions to the model proposed by Wood et al, where EBNA2A directly regulates miR-155HG expression and indirectly regulates miR-155HG expression through the upregulation of both LMP1 and IRF4 (Wood et al, 2018). In this updated model, LMP1 can then activate or support miR-155 expression in the following ways: by PI3K p110α activation of IRF4 (Wang et al, 2011;Wood et al, 2018), by NF-κB activation (Gatto et al, 2008;Rahadiani et al, 2008;Yin et al, 2016), by p38 activation (Rahadiani et al, 2008), and by AP-1 activation (Gatto et al, 2008;Rahadiani et al, 2008;Yin et al, 2008Yin et al, , 2016. As LMP2a also activates similar signaling pathways to LMP1, including the PI3K pathway, further examination of how these four EBV genes cooperate with each other and host signaling pathways to regulate miR-155 expression is warranted.…”

Section: A B C Dsupporting

confidence: 65%

“…Notably, both Src and PI3K are required for activation of IRF4 by LMP1 (Wang et al, 2016), and IRF4 is required to regulate expression of the primary transcript of miR-155, miR-155HG or BIC, in EBV-transformed cells (Wang et al, 2011;Wood et al, 2018). Finally, LMP1 is one of four EBV genes, including LMP2a, EBNA2, and EBNA3C, which have been demonstrated to regulate miR-155 expression (Gatto et al, 2008;Lu et al, 2008;Rahadiani et al, 2008;Yin et al, 2008Yin et al, , 2016Du et al, 2011;Wang et al, 2011;Wood et al, 2018). Collectively, our data and that of Wang et al suggest additions to the model proposed by Wood et al, where EBNA2A directly regulates miR-155HG expression and indirectly regulates miR-155HG expression through the upregulation of both LMP1 and IRF4 (Wood et al, 2018).…”

Section: A B C Dmentioning

confidence: 99%

“…Four EBV genes can regulate miR-155 expression -the latent membrane proteins 1 and 2a (LMP1 and LMP2a) and the EBV nuclear antigens 2 and 3C (EBNA2 and EBNA3C; Gatto et al, 2008;Lu et al, 2008;Rahadiani et al, 2008;Yin et al, 2008Yin et al, , 2016Du et al, 2011;Wang et al, 2011;Wood et al, 2018). These EBV latent genes co-operatively regulate miR-155 expression by activating host cell signaling pathways and transcription factors, such as NF-κB (Gatto et al, 2008;Rahadiani et al, 2008;Yin et al, 2016), p38 (Rahadiani et al, 2008), IRF4 (Wang et al, 2011;Wood et al, 2018), and AP-1 (Gatto et al, 2008;Rahadiani et al, 2008;Yin et al, 2008Yin et al, , 2016, by activating expression of other latent EBV genes (Wood et al, 2018) or by directly interacting with the regulatory regions of the miR-155 host gene (miR-155HG; Wood et al, 2018). For example, EBNA2 regulates expression of miR-155HG both directly, by binding an enhancer region upstream of the miR-155HG locus, and indirectly, by upregulating the expression of LMP1 and the transcription factor IRF4 (Wood et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Epstein-Barr Virus Latent Membrane Protein 1 Regulates Host B Cell MicroRNA-155 and Its Target FOXO3a via PI3K p110α Activation

et al. 2019

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Epstein-Barr Virus (EBV) is associated with potentially fatal lymphoproliferations such as post-transplant lymphoproliferative disorder (PTLD), a serious complication of transplantation. The viral mechanisms underlying the development and maintenance of EBV+ B cell lymphomas remain elusive but represent attractive therapeutic targets. EBV modulates the expression of host microRNAs (miRs), non-coding RNAs that regulate gene expression, to promote survival of EBV+ B cell lymphomas. Here, we examined how the primary oncogene of EBV, latent membrane protein 1 (LMP1), regulates host miRs using an established model of inducible LMP1 signaling. LMP1 derived from the B95.8 lab strain or PTLD induced expression of the oncogene miR-155. However, PTLD variant LMP1 lost the ability to upregulate the tumor suppressor miR-193. Small molecule inhibitors (SMI) of p38 MAPK, NF-κB, and PI3K p110α inhibited upregulation of miR-155 by B95.8 LMP1; no individual SMI significantly reduced upregulation of miR-155 by PTLD variant LMP1. miR-155 was significantly elevated in EBV+ B cell lymphoma cell lines and associated exosomes and inversely correlated with expression of the miR-155 target FOXO3a in cell lines. Finally, LMP1 reduced expression of FOXO3a, which was rescued by a PI3K p110α SMI. Our data indicate that tumor variant LMP1 differentially regulates host B cell miR expression, suggesting viral genotype as an important consideration for the treatment of EBV+ B cell lymphomas. Notably, we demonstrate a novel mechanism in which LMP1 supports the regulation of miR-155 and its target FOXO3a in B cells through activation of PI3K p110α. This mechanism expands on the previously established mechanisms by which LMP1 regulates miR-155 and FOXO3a and may represent both rational therapeutic targets and biomarkers for EBV+ B cell lymphomas.

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supporting

confidence: 94%

Section: A B C Dsupporting

confidence: 65%

Section: A B C Dmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Epstein-Barr Virus Latent Membrane Protein 1 Regulates Host B Cell MicroRNA-155 and Its Target FOXO3a via PI3K p110α Activation

et al. 2019

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“…EBV can for a long time exist in B-lymphocytes and epitheliocytes of nasopharyngeal area and salivary glands. In acute or active infection lytic viral replication dominates [18,19]. EBV proteins, synthesized at the early lytic infection stage, called early antigen complex, are expressed prior to DNA synthesis beginning, some of these proteins are associated with DNA replication.…”

Section: Introductionmentioning

confidence: 99%

On Epstein-Barr Virus Activation in Lymphoid and Epithelial Cancer Cells

Astakhova¹,

Matskova²,

Ernberg³

2016

Science Evolution

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Symbiotic microbiota system functions in homeostasis maintenance of organism are performed through production of multiple microbial low-molecular-weight compounds. Short-chain fatty acids (SCFAs) have a special and multifunctional role among similar compounds. The most important SCFA is a butyric acid which provides barrier and metabolic functions mainly in large intestine. Hyperacetylasion of histones due to histone deacetylase (HDAC) inhibition is one of the key mechanisms, by dint of which the butyric acid influences biologically the large intestine atypical cells. Butyric acid influence at the molecular level is studied insufficiently, in particular, even taking into account all positive effects, there is a danger of reactivation of latent infections which are in cells in their latent form and which may enter acute lytic phase when the transcriptional apparatus is activated. This article presents the study results of butyric acid mechanisms of influence on replication process of Epstein-Barr virus in cancer cells of different origin. It is demonstrated that under the butyric acid influence in epithelial and lymphoid cells transition from latent virus phase to lytic one takes place by means of BZLF-1 and BRLF-1 genes activation. Besides, the butyric acid inhibiting effect on epithelial nasopharynx cancer cells migration in vitro is demonstrated. Based on the obtained data, conclusions were made concerning practicability of butyric acid studying for further use as a functional product in the fight against cancer.Please cite this article in press as: Astakhova L.A., Matskova L.V., Ernberg I. The studying of butyric acid influenceon Epstein-Barr virus activation in lymphoid and epithelial cancer cells.

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The AP‐1 pathway; A key regulator of cellular transformation modulated by oncogenic viruses

Mirzaei

Khodadad

Karami

et al. 2019

Reviews in Medical Virology

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SummaryCancer progression is critically associated with modulation of host cell signaling pathways. Activator protein‐1 (AP‐1) signaling is one such pathway whose deregulation renders the host more susceptible to cancer development. Oncogenic viruses, including hepatitis B virus, hepatitis C virus, human papilloma virus, Epstein‐Barr virus, human T‐cell lymphotropic virus type 1, and Kaposi's sarcoma‐associated herpes virus, are common causes of cancer. This review discusses how these oncoviruses by acting through various aspects of the host cell signaling machinery such as the AP‐1 pathway might affect oncoviral tumorigenesis, replication, and pathogenesis. The review also briefly considers how the pathway might be targeted during infections with these oncogenic viruses.

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Methylation status and AP1 elements are involved in EBV-mediated miR-155 expression in EBV positive lymphoma cells

Cited by 19 publications

References 50 publications

Epstein-Barr Virus Latent Membrane Protein 1 Regulates Host B Cell MicroRNA-155 and Its Target FOXO3a via PI3K p110α Activation

Epstein-Barr Virus Latent Membrane Protein 1 Regulates Host B Cell MicroRNA-155 and Its Target FOXO3a via PI3K p110α Activation

On Epstein-Barr Virus Activation in Lymphoid and Epithelial Cancer Cells

The AP‐1 pathway; A key regulator of cellular transformation modulated by oncogenic viruses

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