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The tumor suppressor gene rap1GAP is silenced by miR-101-mediated EZH2 overexpression in invasive squamous cell

R Banerjee1, R-S Mani, N Russo

  • 1Department of Periodontics and Oral Medicine, Medical School, University of Michigan, Ann Arbor, MI 48109-1078, USA.

Oncogene
|May 3, 2011
PubMed

Insights

Rap1GAP, a tumor suppressor, is repressed by EZH2 in head and neck cancers. Loss of miR-101 correlates with EZH2 upregulation, driving cancer progression via a microRNA-oncogene-tumor suppressor axis.

Area of Science:

  • Molecular oncology
  • Epigenetics
  • Cancer biology

Background:

  • Rap1GAP is a crucial tumor suppressor gene frequently downregulated in aggressive cancers like head and neck squamous cell carcinoma.
  • The precise mechanisms driving Rap1GAP downregulation in cancer remain largely undefined.

Purpose of the Study:

  • To elucidate the mechanistic basis of Rap1GAP downregulation in head and neck cancers.
  • To investigate the role of polycomb repression and microRNA in regulating Rap1GAP expression.

Main Methods:

  • Integrative genomic and epigenomic analyses.
  • ChIP-sequencing for histone modifications.
  • Quantitative PCR for gene and microRNA expression.
  • Promoter methylation analysis.

Main Results:

  • Polycomb-mediated repression of Rap1GAP was identified, involving Enhancer of Zeste Homolog 2 (EZH2) in head and neck cancers.
  • Loss of miR-101 expression correlated with increased EZH2 levels and decreased Rap1GAP expression.
  • EZH2 facilitates Rap1GAP repression through histone H3 trimethylation at lysine 27 and promoter hypermethylation.

Conclusions:

  • A novel microRNA-oncogene-tumor suppressor axis (miR-101/EZH2/Rap1GAP) contributes to head and neck cancer progression.
  • Epigenetic silencing by EZH2 is a key mechanism for Rap1GAP tumor suppressor loss.
  • Understanding this axis offers potential therapeutic targets for head and neck cancers.

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