Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP

Cancer Cell. 2014 Jun 16;25(6):822-30. doi: 10.1016/j.ccr.2014.04.017. Epub 2014 May 29.

Abstract

Uveal melanoma (UM) is the most common cancer in adult eyes. Approximately 80% of UMs harbor somatic activating mutations in GNAQ or GNA11 (encoding Gq or G11, respectively). Herein, we show in both cell culture and human tumors that cancer-associated Gq/11 mutants activate YAP, a major effector of the Hippo tumor suppressor pathway that is also regulated by G protein-coupled receptor signaling. YAP mediates the oncogenic activity of mutant Gq/11 in UM development, and the YAP inhibitor verteporfin blocks tumor growth of UM cells containing Gq/11 mutations. This study reveals an essential role of the Hippo-YAP pathway in Gq/11-induced tumorigenesis and suggests YAP as a potential drug target for UM patients carrying mutations in GNAQ or GNA11.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Cycle Proteins
  • Cell Growth Processes / genetics
  • Cell Line, Tumor
  • Disease Models, Animal
  • Down-Regulation
  • GTP-Binding Protein alpha Subunits, Gq-G11 / genetics*
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
  • HEK293 Cells
  • Humans
  • Male
  • Melanoma / genetics*
  • Melanoma / metabolism
  • Melanoma / pathology
  • Mice
  • Mice, Nude
  • Mice, SCID
  • Mutation*
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • Signal Transduction
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transfection
  • Uveal Neoplasms / genetics*
  • Uveal Neoplasms / metabolism
  • Uveal Neoplasms / pathology

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Phosphoproteins
  • Transcription Factors
  • YY1AP1 protein, human
  • Yap1 protein, mouse
  • GTP-Binding Protein alpha Subunits, Gq-G11

Supplementary concepts

  • Uveal melanoma