VGLL4 functions as a new tumor suppressor in lung cancer by negatively regulating the YAP-TEAD transcriptional complex

Cell Res. 2014 Mar;24(3):331-43. doi: 10.1038/cr.2014.10. Epub 2014 Jan 24.

Abstract

Lung cancer is one of the most devastating diseases worldwide with high incidence and mortality. Hippo (Hpo) pathway is a conserved regulator of organ size in both Drosophila and mammals. Emerging evidence has suggested the significance of Hpo pathway in cancer development. In this study, we identify VGLL4 as a novel tumor suppressor in lung carcinogenesis through negatively regulating the formation of YAP-TEAD complex, the core component of Hpo pathway. Our data show that VGLL4 is frequently observed to be lowly expressed in both mouse and human lung cancer specimens. Ectopic expression of VGLL4 significantly suppresses the growth of lung cancer cells in vitro. More importantly, VGLL4 significantly inhibits lung cancer progression in de novo mouse model. We further find that VGLL4 inhibits the activity of the YAP-TEAD transcriptional complex. Our data show that VGLL4 directly competes with YAP in binding to TEADs and executes its growth-inhibitory function through two TDU domains. Collectively, our study demonstrates that VGLL4 is a novel tumor suppressor for lung cancer through negatively regulating the YAP-TEAD complex formation and thus the Hpo pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology*
  • Animals
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Proliferation
  • Disease Models, Animal
  • Down-Regulation
  • HEK293 Cells
  • Humans
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Mice
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Protein Binding
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic

Substances

  • Cell Cycle Proteins
  • Nuclear Proteins
  • RNA, Small Interfering
  • Transcription Factors
  • VGLL4 protein, human
  • YY1AP1 protein, human
  • Hippo protein, human
  • Protein-Serine-Threonine Kinases