Abstract
Increasing evidence suggests that Kaposi's sarcoma (KS) arises from Kaposi's sarcoma-associated herpesvirus (KSHV)-infected mesenchymal stem cells (MSCs) through mesenchymal-to-endothelial transition (MEndT). KSHV infection promotes MSC differentiation of endothelial lineage and acquisition of tumorigeneic phenotypes. To understand how KSHV induces MEndT and transforms MSCs to KS cells, we investigated the mechanism underlying KSHV-mediated MSC endothelial lineage differentiation. Like embryonic stem cells, MSC differentiation and fate determination are under epigenetic control. Prospero homeobox 1 (PROX1) is a master regulator that controls lymphatic vessel development and endothelial differentiation. We found that the PROX1 gene in MSCs harbors a distinctive bivalent epigenetic signature consisting of both active marker H3K4me3 and repressive marker H3K27me3, which poises expression of the genes, allowing timely activation upon differentiation signals or environmental stimuli. KSHV infection effectively resolves the bivalent chromatin by decreasing H3K27me3 and increasing H3K4me3 to activate the PROX1 gene. vIL-6 signaling leads to the recruitment of MLL2 and SET1 complexes to the PROX1 promoter to increase H3K4me3, and the vGPCR-VEGF-A axis is responsible for removing PRC2 from the promoter to reduce H3K27me3. Therefore, through a dual signaling process, KSHV activates PROX1 gene expression and initiates MEndT, which renders MSC tumorigenic features including angiogenesis, invasion and migration.
Highlights
Kaposi’s sarcoma-associated herpesvirus (KSHV), termed human herpesvirus type 8 (HHV8), has been proven to be the etiological agent of Kaposi’s sarcoma (KS) [1], primary effusion lymphoma (PEL) [2], and multicentric Castleman’s disease (MCD) [3]
To confirm that KSHV infection is responsible for the induction of Prospero homeobox 1 (PROX1) expression, we examined three cases of KS, one oral and two skin lesions for expression of PROX1 and KSHV antigen LANA using immunohistochemistry analysis
Periodontal ligament stem cells (PDLSCs) were infected with KSHV and the expression of PROX1 in response to KSHV infection was examined by double-staining immunofluorescence assay (IFA) and Western analysis
Summary
Kaposi’s sarcoma-associated herpesvirus (KSHV), termed human herpesvirus type 8 (HHV8), has been proven to be the etiological agent of Kaposi’s sarcoma (KS) [1], primary effusion lymphoma (PEL) [2], and multicentric Castleman’s disease (MCD) [3]. KSHV was found to be associated with childhood osteosarcoma in Xinjiang Uyghur population [4]. The lack of comprehensive understanding about KSHV infection and tumorigenesis hampers our ability to treat KSHV-associated cancers. The origin of KS spindle cells remains elusive. The current leading model is that KS spindle cells may derive from endothelial cell lineage as KS cells express endothelial markers. KS cells are poorly differentiated and express other markers such as smooth muscle, macrophage, and mesenchymal markers, suggesting that KS cells do not faithfully represent the endothelial cell lineage [5]. We found a series of evidence suggesting that KS originates from oral mesenchymal stem cells (MSCs) through KSHV-induced mesenchymal-to-endothelial transition (MEndT) [6]
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