Abstract
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.
Highlights
Kaposi’s sarcoma (KS), a highly angiogenic and disseminated tumor of endothelial cells commonly found in AIDS patients, is caused by infection of a human oncogenic virus Kaposi’s sarcoma-associated herpesvirus (KSHV)
We reveal that viral interferon regulatory factor 1 (vIRF1) enhances Sperm associated antigen 9 (SPAG9) transcription by forming a transcription factor complex with Lef1. vIRF1-induced SPAG9 upregulation promotes the interaction of mitogen-activated protein kinase kinase 4 (MKK4) with Jun-terminal kinase (JNK) together leading to enhanced JNK phosphorylation
This work discovers a novel mechanism of vIRF1 induction of angiogenesis and tumorigenesis, and reveals SPAG9/JNK/VEGFA pathway as a potential target for KS therapy
Summary
Kaposi’s sarcoma (KS), a highly angiogenic and disseminated tumor of endothelial cells commonly found in AIDS patients, is caused by infection of a human oncogenic virus Kaposi’s sarcoma-associated herpesvirus (KSHV). KSHV encodes several cellular homologues, including viral interferon regulatory factors (vIRFs) [5], viral G protein-coupled receptor (vGPCR) [6], viral cyclin (vCyclin) [7], viral interleukin-6 (vIL-6) [8], viral Bcl-2 (vBcl-2) [9], and viral FLICE inhibitory protein (vFLIP) [10]. These proteins promote cell proliferation and survival, evade immune responses and induce inflammation, contributing to the development and progression of KSHV-induced tumors [11]
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