Viral interleukin-6 encoded by an oncogenic virus promotes angiogenesis and cellular transformation by enhancing STAT3-mediated epigenetic silencing of caveolin 1

Wan, Li; Wang, Qingxia; Qi, Xiaoyu; Guo, Yuanyuan; Lü, Hongmei; Chen, Yuheng; Lu, Zhaoyi; Yan, Qin; Zhu, Xiaofei; Jung, Jae U.; Tosato, Giovanna; Gao, Shou‐Jiang; Liu, Chun

doi:10.1038/s41388-020-1317-1

Cited by 28 publications

(27 citation statements)

References 51 publications

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“…This is likely due to the fact that other KSHV proteins and miRNAs might also induce JNK activation. These include miR-K6-3p [54], miR-K3 [55], viral FLICE-inhibitory protein (vFLIP) [56], viral interleukin-6 (vIL-6) [57], and ORF-K15 [58]. In agreement with these results, KSHV infection induces faster cell proliferation and cell migration than vIRF1 does.…”

Section: Plos Pathogenssupporting

confidence: 66%

Sperm associated antigen 9 promotes oncogenic KSHV-encoded interferon regulatory factor-induced cellular transformation and angiogenesis by activating the JNK/VEGFA pathway

Wan¹,

Wang²,

Shi³

et al. 2020

PLoS Pathog

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Kaposi's sarcoma (KS), caused by Kaposi's sarcoma-associated herpesvirus (KSHV), is a highly angioproliferative disseminated tumor of endothelial cells commonly found in AIDS patients. We have recently shown that KSHV-encoded viral interferon regulatory factor 1 (vIRF1) mediates KSHV-induced cell motility (PLoS Pathog. 2019 Jan 30;15(1):e1007578). However, the role of vIRF1 in KSHV-induced cellular transformation and angiogenesis remains unknown. Here, we show that vIRF1 promotes angiogenesis by upregulating sperm associated antigen 9 (SPAG9) using two in vivo angiogenesis models including the chick chorioallantoic membrane assay (CAM) and the matrigel plug angiogenesis assay in mice. Mechanistically, vIRF1 interacts with transcription factor Lef1 to promote SPAG9 transcription. vIRF1-induced SPAG9 promotes the interaction of mitogen-activated protein kinase kinase 4 (MKK4) with JNK1/2 to increase their phosphorylation, resulting in enhanced VEGFA expression, angiogenesis, cell proliferation and migration. Finally, genetic deletion of ORF-K9 from KSHV genome abolishes KSHV-induced cellular transformation and impairs angiogenesis. Our results reveal that vIRF1 transcriptionally activates SPAG9 expression to promote angiogenesis and tumorigenesis via activating JNK/VEGFA signaling. These novel findings define the mechanism of KSHV induction of the SPAG9/JNK/ VEGFA pathway and establish the scientific basis for targeting this pathway for treating KSHV-associated cancers.

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Section: Plos Pathogenssupporting

confidence: 66%

Sperm associated antigen 9 promotes oncogenic KSHV-encoded interferon regulatory factor-induced cellular transformation and angiogenesis by activating the JNK/VEGFA pathway

Wan¹,

Wang²,

Shi³

et al. 2020

PLoS Pathog

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“…Two other KSHV proteins interfere with DNA methylation. vIRF1 could upregulate DNMT1 expression in a STAT3-dependent manner and by inhibiting p53 [ 47 , 49 ]. vIL6-induced modifications in DNA methylation promoted proliferation and migration of endothelial cells [ 47 ].…”

Section: Oncoviruses and Host Cell Dna Methylationmentioning

confidence: 99%

“…vIL6-induced modifications in DNA methylation promoted proliferation and migration of endothelial cells [ 47 ]. Another group showed that the vIL6/STAT3/DNMT1 axis was involved in silencing expression of caveolin 1, which promoted cell proliferation, invasion and angiogenesis of endothelial cells [ 49 ]. The mechanism by which KSHV achieves hypomethylation of the host DNA is not known.…”

Section: Oncoviruses and Host Cell Dna Methylationmentioning

confidence: 99%

Role of Virus-Induced Host Cell Epigenetic Changes in Cancer

Pietropaolo¹,

Prezioso

Moens

2021

IJMS

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The tumor viruses human T-lymphotropic virus 1 (HTLV-1), hepatitis C virus (HCV), Merkel cell polyomavirus (MCPyV), high-risk human papillomaviruses (HR-HPVs), Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpes virus (KSHV) and hepatitis B virus (HBV) account for approximately 15% of all human cancers. Although the oncoproteins of these tumor viruses display no sequence similarity to one another, they use the same mechanisms to convey cancer hallmarks on the infected cell. Perturbed gene expression is one of the underlying mechanisms to induce cancer hallmarks. Epigenetic processes, including DNA methylation, histone modification and chromatin remodeling, microRNA, long noncoding RNA, and circular RNA affect gene expression without introducing changes in the DNA sequence. Increasing evidence demonstrates that oncoviruses cause epigenetic modifications, which play a pivotal role in carcinogenesis. In this review, recent advances in the role of host cell epigenetic changes in virus-induced cancers are summarized.

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“…vIL-6 is a homolog of the human cytokine and binds the human IL-6 receptor [ 23 ]. Among its many functions, recent studies have shown that vIL-6 increases expression of integrin β3 [ 24 ] and decreases expression of caveolin 1 [ 25 ] through its activation of STAT3. Both changes contribute to angiogenic-like behavior in cells expressing vIL-6.…”

Section: What Is the Contribution Of Lytic Replication To Tumorigenesis?mentioning

confidence: 99%

Kaposi's sarcoma-associated herpesvirus at 27

Gaglia

2021

Tumour Virus Research

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Kaposi's sarcoma-associated herpesvirus (KSHV) was discovered 27 years ago and its link to several pathologies – Kaposi's sarcoma, primary effusion lymphoma, and the B cell variant of Multicentric Castleman disease – is now well established. However, many questions remain about how KSHV causes tumors. Here, I will review studies from the last few years (primarily 2019–2021) that report new information about KSHV biology and tumorigenesis, including new results about KSHV proteins implicated in tumorigenesis, genetic and environmental variability in KSHV-related tumor development, and potential vulnerabilities of KSHV-caused tumors that could be novel therapeutic targets.

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Viral interleukin-6 encoded by an oncogenic virus promotes angiogenesis and cellular transformation by enhancing STAT3-mediated epigenetic silencing of caveolin 1

Cited by 28 publications

References 51 publications

Sperm associated antigen 9 promotes oncogenic KSHV-encoded interferon regulatory factor-induced cellular transformation and angiogenesis by activating the JNK/VEGFA pathway

Sperm associated antigen 9 promotes oncogenic KSHV-encoded interferon regulatory factor-induced cellular transformation and angiogenesis by activating the JNK/VEGFA pathway

Role of Virus-Induced Host Cell Epigenetic Changes in Cancer

Kaposi's sarcoma-associated herpesvirus at 27

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