Epigenetic control in Kaposi sarcoma-associated herpesvirus infection and associated disease

Fröhlich, Jacqueline; Grundhoff, Adam

doi:10.1007/s00281-020-00787-z

Cited by 27 publications

(36 citation statements)

References 141 publications

(191 reference statements)

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“…Reports of KS lesions displaying variable percentage of KSHV infected (LANA positive) cells [2,4,22] point to the occurrence of KS-spindle cells that have lost the KSHV-episome. This is consistent with studies showing spontaneous KSHV-episome loss in cultures, and the proposed need of continuous re-infection in the KS-lesions and/or paracrine stimulation from infected cells [22,24,25]. Yet, since our studies have shown that the KSHV-episome is retained during tumor formation because it provides a growth advantage, the existence of KSHV-negative phospho-PDGFRA positive spindle cells in KS lesions also suggest the possibility of a virus-independent "hit and run" mechanisms of sarcomagenesis.…”

Section: Introductionsupporting

confidence: 91%

High-throughput sequencing analysis of a “hit and run” cell and animal model of KSHV tumorigenesis

et al. 2020

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Kaposi's sarcoma (KS), is an AIDS-associated neoplasm caused by the KS herpesvirus (KSHV/ HHV-8). KSHV-induced sarcomagenesis is the consequence of oncogenic viral gene expression as well as host genetic and epigenetic alterations. Although KSHV is found in all KS-lesions, the percentage of KSHV-infected (LANA+) spindle-cells of the lesion is variable, suggesting the existence of KS-spindle cells that have lost KSHV and proliferate autonomously or via paracrine mechanisms. A mouse model of KSHVBac36-driven tumorigenesis allowed us to induce KSHV-episome loss before and after tumor development. Although infected cells that lose the KSHV-episome prior to tumor formation lose their tumorigenicity, explanted tumor cells that lost the KSHV-episome remained tumorigenic. This pointed to the existence of virally-induced irreversible oncogenic alterations occurring during KSHV tumorigenesis supporting the possibility of hit and run viral-sarcomagenesis. RNA-sequencing and CpG-methylation analysis were performed on KSHV-positive and KSHV-negative tumors that developed following KSHV-episome loss from explanted tumor cells. When KSHV-positive cells form KSHV-driven tumors, along with viral-gene upregulation there is a tendency for hypo-methylation in genes from oncogenic and differentiation pathways. In contrast, KSHV-negative tumors formed after KSHV-episome loss, show a tendency towards gene hyper-methylation when compared to KSHV-positive tumors. Regarding occurrence of host-mutations, we found the same set of innate-immunity related mutations undetected in KSHV-infected cells but present in all KSHV-positive tumors occurring en exactly the same position, indicating that pre-existing host mutations that provide an in vivo growth advantage are clonally-selected and contribute to KSHV-tumorigenesis. In addition, KSHV-negative tumors display de novo mutations related to cell proliferation that, together with the PDGFRAD842V and other proposed mechanism, could be responsible for

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Section: Introductionsupporting

confidence: 91%

High-throughput sequencing analysis of a “hit and run” cell and animal model of KSHV tumorigenesis

et al. 2020

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“…KSHV pathogenesis is associated with the latent infection where the viral genome persists as a multi-copy circular genome, referred to as the episome, in the nucleus of an infected cell [ 3 , 4 ]. The viral episomes are subject to chromatin assembly and epigenetic regulation that restrict viral gene expression to only a few viral genes, yet remain poised for rapid reactivation to complete the viral life cycle [ 5 – 7 ]. During latency, viral transcription and replication depend on host machinery.…”

Section: Introductionmentioning

confidence: 99%

Phase separation and DAXX redistribution contribute to LANA nuclear body and KSHV genome dynamics during latency and reactivation

et al. 2021

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Liquid-liquid phase separation (LLPS) can drive formation of diverse and essential macromolecular structures, including those specified by viruses. Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) genomes associate with the viral encoded Latency-Associated Nuclear Antigen (LANA) to form stable nuclear bodies (NBs) during latent infection. Here, we show that LANA-NB formation and KSHV genome conformation involves LLPS. Using LLPS disrupting solvents, we show that LANA-NBs are partially disrupted, while DAXX and PML foci are highly resistant. LLPS disruption altered the LANA-dependent KSHV chromosome conformation but did not stimulate lytic reactivation. We found that LANA-NBs undergo major morphological transformation during KSHV lytic reactivation to form LANA-associated replication compartments encompassing KSHV DNA. DAXX colocalizes with the LANA-NBs during latency but is evicted from the LANA-associated lytic replication compartments. These findings indicate the LANA-NBs are dynamic super-molecular nuclear structures that partly depend on LLPS and undergo morphological transitions corresponding the different modes of viral replication.

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“…Similar epigenetic modulation has been observed in other virally-induced cancers such as B cell lymphoproliferative diseases by KSHV infection. In KSHV, several genes that function in epigenetic inactivation are suppressed by the interaction of LANA and DNA methyltransferase DNMT3a, LANA and TGF-β type II receptor, and KSHV miRNA induces oncogene expression [ 107 ]. Reversing the actions of viral-induced epigenetic modifications could provide alternative targets to eradicate infection.…”

Section: Viral Infection Epigenetics and Aberrant Splicingmentioning

confidence: 99%

Aberrant Splicing Events and Epigenetics in Viral Oncogenomics: Current Therapeutic Strategies

Francies

Dlamini

2021

Cells

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Global cancer incidence and mortality are on the rise. Although cancer is fundamentally a non-communicable disease, a large number of cancers are known to have a viral aetiology. A high burden of infectious agents (Human immunodeficiency virus (HIV), human papillomavirus (HPV), hepatitis B virus (HBV)) in certain Sub-Saharan African countries drives the rates of certain cancers. About one-third of all cancers in Africa are attributed to infection. Seven viruses have been identified with carcinogenic characteristics, namely the HPV, HBV, Hepatitis C virus (HCV), Epstein–Barr virus (EBV), Human T cell leukaemia virus 1 (HTLV-1), Kaposi’s Sarcoma Herpesvirus (KSHV), and HIV-1. The cellular splicing machinery is compromised upon infection, and the virus generates splicing variants that promote cell proliferation, suppress signalling pathways, inhibition of tumour suppressors, alter gene expression through epigenetic modification, and mechanisms to evade an immune response, promoting carcinogenesis. A number of these splice variants are specific to virally-induced cancers. Elucidating mechanisms underlying how the virus utilises these splice variants to maintain its latent and lytic phase will provide insights into novel targets for drug discovery. This review will focus on the splicing genomics, epigenetic modifications induced by and current therapeutic strategies against HPV, HBV, HCV, EBV, HTLV-1, KSHV and HIV-1.

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Epigenetic control in Kaposi sarcoma-associated herpesvirus infection and associated disease

Cited by 27 publications

References 141 publications

High-throughput sequencing analysis of a “hit and run” cell and animal model of KSHV tumorigenesis

High-throughput sequencing analysis of a “hit and run” cell and animal model of KSHV tumorigenesis

Phase separation and DAXX redistribution contribute to LANA nuclear body and KSHV genome dynamics during latency and reactivation

Aberrant Splicing Events and Epigenetics in Viral Oncogenomics: Current Therapeutic Strategies

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