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

G. Liu, F. X. Yu, Y. C. Kim, Z. Meng, J. Naipauer, D. J. Looney, X. Liu, J. S. Gutkind, Enrique A Mesri, K. L. Guan

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39 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3536-3546
Number of pages11
JournalOncogene
Volume34
Issue number27
DOIs
StatePublished - Jul 1 2015

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ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

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. (2015). Kaposi sarcoma-associated herpesvirus promotes tumorigenesis by modulating the Hippo pathway. Oncogene, 34(27), 3536-3546. https://doi.org/10.1038/onc.2014.281