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

Oncogene. 2015 Jul;34(27):3536-46. doi: 10.1038/onc.2014.281. Epub 2014 Sep 8.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Cycle Proteins
  • Cell Transformation, Viral / genetics*
  • Cells, Cultured
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Herpesvirus 8, Human / physiology*
  • Humans
  • Mice
  • Mice, Nude
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Sarcoma, Kaposi / genetics
  • Sarcoma, Kaposi / metabolism
  • Sarcoma, Kaposi / pathology
  • Signal Transduction / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Cell Cycle Proteins
  • Nuclear Proteins
  • TAZ protein, human
  • Transcription Factors
  • YY1AP1 protein, human
  • Hippo protein, human
  • Protein-Serine-Threonine Kinases