Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of several human cancers such as Kaposi’s sarcoma (KS), which represents the most common AIDS-associated malignancy that lacks effective treatment options. Despite its clear role in AIDS malignancies, the fact that only a small set of KSHV-infected patients will eventually develop these tumors implies that additional co-factors are required for the development of KSHV-related cancers. In the current study, we demonstrate for the first time that KSHV de novo infection or viral latent proteins are able to transactivate human endogenous retrovirus K (HERV-K) through a variety of cellular signaling pathways and transcriptional factors. Moreover, we found that HERV-K transactivation, particularly activation of its encoded oncogenic NP9 protein, plays an important role in KSHV pathogenesis and tumorigenesis in vitro and in vivo. Our data provide innovative insights into the mechanisms of HERV-K transactivation contributing to viral oncogenesis, which may represent a promising target for KS treatment.
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We thank Dr. Rolf Renne at the University of Florida for his kind gifts of TIVE-LTC and TIVE cells and Dr. Friedrich A. Grasser from Universitatsklinikum des Saarlandes, Germany for kindly providing HERV-K NP9 plasmids and antibody. This work was supported by grants from a DOD Career Development Award to (CA140437 to ZQ); a Louisiana Clinical and Translational Science Center Pilot grant (U54GM104940 from NIH), a LSU LIFT2 funding, and NIH P20-GM121288-01 (PI: Krzysztof Reiss) subproject to ZQ; NIH RO1-AI101046, R01-AI106676, and P01CA214091 and Department of Defense W81XWH-16-1-0318 to EKF; the federal funds from the National Cancer Institute, NIH, under Contract No. HHSN261200800001E to DW; and the awards from the National Natural Science Foundation of China (81472547, 81672924 to ZQ and 81400164, 81772930 to LD). Funding sources had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
LD and ZQ designed and performed experiments, analyzed results, and wrote the manuscript. LDV and WM performed experiments. DW, ACO, and EKF performed statistical analysis and provided critical input.
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The authors declare that they have no conflict of interest.
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Dai, L., Del Valle, L., Miley, W. et al. Transactivation of human endogenous retrovirus K (HERV-K) by KSHV promotes Kaposi’s sarcoma development. Oncogene 37, 4534–4545 (2018). https://doi.org/10.1038/s41388-018-0282-4
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