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Regulation of c-met expression by transcription repressor Daxx

V M Morozov1, N A Massoll, O V Vladimirova

  • 1Department of Anatomy & Cell Biology and Shands Cancer Center, University of Florida, Gainesville, FL, USA.

Oncogene
|October 24, 2007
PubMed

Insights

Daxx acts as a repressor of c-met transcription. Loss of Daxx increases c-met expression and enhances cancer cell invasion, suggesting Daxx

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Gene Regulation

Background:

  • The protooncogene c-met encodes a tyrosine kinase receptor involved in cell growth and motility.
  • Overexpression of c-met is frequently observed in various tumors, but its regulatory mechanisms are not fully understood.
  • Hepatocyte growth factor/scatter factor (HGF/SF) is the ligand for the c-Met receptor.

Purpose of the Study:

  • To investigate the role of Daxx in the transcriptional regulation of the c-met protooncogene.
  • To elucidate the molecular mechanisms by which Daxx may control c-met expression.
  • To explore the functional consequences of altered c-met regulation by Daxx in cancer progression.

Main Methods:

  • Analysis of c-met expression in Daxx knockout and reconstituted mouse cells.
  • Chromatin analysis (acetylation and methylation) of the c-met promoter.
  • Chromatin immunoprecipitation (ChIP) assays to detect Daxx and HDAC2 binding to the c-met promoter.
  • Assessment of HGF-induced cell mobility and invasion assays.
  • Correlation analysis of Daxx and c-Met expression in cancer cell lines and patient specimens.

Main Results:

  • Daxx functions as a repressor of c-met transcription.
  • c-met expression is significantly elevated in Daxx-deficient cells, with restoration of Daxx reversing this effect.
  • Daxx binds to the c-met promoter, and this interaction is associated with changes in chromatin acetylation.
  • Daxx-dependent recruitment of HDAC2 to the c-met promoter is implicated in transcriptional repression.
  • Daxx-deficient cells exhibit enhanced HGF-induced cell motility and invasion.
  • An inverse correlation between Daxx and c-Met levels was observed in cancer cell lines and metastatic breast cancer tissues.

Conclusions:

  • Daxx represses c-met transcription, likely through recruitment of HDAC2 and modulation of chromatin structure.
  • The loss of Daxx-mediated repression of c-met may contribute to increased cancer cell invasion and progression.
  • Daxx represents a potential tumor suppressor in the context of c-met-driven cancers.

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