Kaposi's Sarcoma associated Herpes-virus induces cellular PROX1 expression to modulate host gene expression that benefits viral infection and oncogenesis

Kaposi Sarcoma (KS) is the most prevalent neoplasm within HIV-infected patients and transplant recipients. Kaposi's Sarcoma-Associated Herpesvirus (KSHV) causes the disease by using a novel mechanism that reprograms endothelial cells making them susceptible targets for viral infection and dissemination. We and others reported that KSHV induces lymphatic differentiation of blood vascular endothelial cells (BECs), by inducing PROX1 up-regulation. Importantly, KSHV G-protein coupled receptor (vGPCR) has been identified as the major viral gene responsible for cellular transformation and disease maintenance. Given that PROX1 is an important mediator of KSHV-induced cell reprogramming, we set out to determine if it had other functional implications in KS pathogenesis. In this study, we report that the regulator of G-protein signaling (RGS)-4 is selectively expressed in BECs and not in LECs, and acts as a cellular agonist against the transformation function of vGPCR. In effect, we found that RGS4 is able to suppress cell proliferation, migration, VEGF-expression and activation of vGPCR-expressing cells in vitro. In accordance, RGS4 significantly antagonized vGPCR-induced tumor growth in two models of immune-deficient mice with reduced tumor-associated angiogenesis. Finally, we demonstrate that KSHV-up-regulated PROX1 and LRH1 cooperate to repress RGS4 expression in KSHV-infected BECs. Together, our study identifies a novel viral strategy that hinders a major host-GPCR regulatory mechanism that may function as an inhibitor for vGPCR activity. Based on our data, we propose a novel hypothesis that KSHV obstructs RGS4-mediated host inhibition of vGPCR transforming activity by up-regulating its transcriptional repressors, PROX1 and LRH1, in order to facilitate KS tumorigenesis.