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, E. A. Mesri, K. L. Guan

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42 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

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    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