Acetylation-dependent oncogenic activity of metastasis-associated protein 1 co-regulator

EMBO Rep. 2010 Sep;11(9):691-7. doi: 10.1038/embor.2010.99. Epub 2010 Jul 23.

Abstract

High expression of metastasis-associated protein 1 co-regulator (MTA1), a component of the nuclear remodelling and histone deacetylase complex, has been associated with human tumours. However, the precise role of MTA1 in tumorigenesis remains unknown. In this study, we show that induced levels of MTA1 are sufficient to transform Rat1 fibroblasts and that the transforming potential of MTA1 is dependent on its acetylation at Lys626. Underlying mechanisms of MTA1-mediated transformation include activation of the Ras-Raf pathway by MTA1 but not by acetylation-inactive MTA1; this was due to the repression of Galphai2 transcription, which negatively influences Ras activation. We observed that acetylated MTA1-histone deacetylase (HDAC) interaction was required for the recruitment of the MTA1-HDAC complex to the Galphai2 regulatory element and consequently for the repression of Galphai2 transcription and expression leading to activation of the Ras-Raf pathway. The findings presented in this study provide for the first time--to the best of our knowledge--evidence of acetylation-dependent oncogenic activity of a cancer-relevant gene product.

Publication types

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

MeSH terms

  • Acetylation
  • Animals
  • Cell Line
  • Cell Movement
  • Cell Transformation, Neoplastic*
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • GTP-Binding Protein alpha Subunit, Gi2 / genetics
  • GTP-Binding Protein alpha Subunit, Gi2 / metabolism
  • Gene Expression Regulation, Neoplastic
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Humans
  • Lysine / metabolism
  • Mice
  • Mice, Nude
  • Neoplasms, Experimental
  • Oncogenes*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Transcription, Genetic
  • Transplantation, Heterologous
  • ras Proteins / genetics
  • ras Proteins / metabolism

Substances

  • Mta1 protein, human
  • Repressor Proteins
  • Histone Deacetylases
  • GTP-Binding Protein alpha Subunit, Gi2
  • ras Proteins
  • Lysine