Kaposi sarcoma-associated herpesvirus promotes tumorigenesis by modulating the Hippo pathway

• Published in: Oncogene 2015-07, Vol.34 (27), p.3536-3546
• Main Authors: Liu, G, Yu, F-X, Kim, Y C, Meng, Z, Naipauer, J, Looney, D J, Liu, X, Gutkind, J S, Mesri, E A, Guan, K-L
• Format: Article
• Language: English
• Subjects: 101/1; 13/51; 13/95; 14/105; 14/19; 45/29; 631/67/1798; 64/60; 96/109; Animals; Apoptosis; Cell Biology; Cell Cycle Proteins; Cell proliferation; Cell Transformation, Viral - genetics; Cells, Cultured; Cellular signal transduction; Development and progression; G protein-coupled receptors; Gene Expression Regulation, Neoplastic; Genetic aspects; Health aspects; HEK293 Cells; Herpes viruses; Herpesvirus; Herpesvirus 8, Human - physiology; Human Genetics; Humans; Internal Medicine; Kaposi's sarcoma; Kaposi's sarcoma-associated herpesvirus; Kaposis sarcoma; Kinases; Malignancy; Medicine; Medicine & Public Health; Mice; Mice, Nude; Neurons; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oncology; original-article; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proteins; Sarcoma; Sarcoma, Kaposi - genetics; Sarcoma, Kaposi - metabolism; Sarcoma, Kaposi - pathology; Signal Transduction - genetics; Transcription Factors - genetics; Transcription Factors - metabolism; Transformed cells; Tumor suppressor genes; Tumorigenesis; Xenografts; Yes-associated protein
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.281

Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic virus and the culprit behind the human disease Kaposi sarcoma (KS), an AIDS-defining malignancy. KSHV encodes a viral G-protein-coupled receptor (vGPCR) critical for the initiation and progression of KS. In this study, we identified that YAP/TAZ, two homologous oncoproteins inhibited by the Hippo tumor suppressor pathway, are activated in KSHV-infected cells in vitro, KS-like mouse tumors and clinical human KS specimens. The KSHV-encoded vGPCR acts through Gq/11 and G12/13 to inhibit the Hippo pathway kinases Lats1/2, promoting the activation of YAP/TAZ. Furthermore, depletion of YAP/TAZ blocks vGPCR-induced cell proliferation and tumorigenesis in a xenograft mouse model. The vGPCR-transformed cells are sensitive to pharmacologic inhibition of YAP. Our study establishes a pivotal role of the Hippo pathway in mediating the oncogenic activity of KSHV and development of KS, and also suggests a potential of using YAP inhibitors for KS intervention.