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Methyl-CpG targeted transcriptional activation allows re-expression of tumor suppressor genes in human cancer cells

Shinichi Fukushige1, Emiko Kondo1, Akira Horii1

  • 1Department of Molecular Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.

Biochemical and Biophysical Research Communications
|October 22, 2008
PubMed

Insights

Methyl-CpG Targeted Transcriptional Activation (MeTA) reactivates tumor suppressor genes in cancer without DNA demethylation. This epigenetic mechanism recruits coactivators to methylated promoters, offering a new strategy for identifying silenced genes.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Molecular Biology

Background:

  • Epigenetic silencing, involving DNA methylation and histone modifications, frequently inactivates tumor suppressor genes (TSGs) in cancer.
  • Current DNA methylation inhibitors can reactivate TSGs but often affect unmethylated genes.
  • Histone deacetylase inhibitors are generally less effective at reactivating TSGs.

Purpose of the Study:

  • To demonstrate the prevalence of methyl-CpG targeted transcriptional activation (MeTA) in human cancer.
  • To elucidate the mechanism by which MeTA reactivates TSGs without requiring DNA demethylation.
  • To establish an efficient method for identifying transcriptionally silenced genes, particularly TSGs and developmentally important genes.

Main Methods:

  • Analysis of MeTA in human cancer samples.
  • Investigating the recruitment of transcriptional coactivators to hypermethylated promoter regions via methyl-CpG binding domains (MBDs).
  • Assessing the reactivation of the MLH1 gene, including histone acetylation changes at its promoter.

Main Results:

  • MeTA was found to be widely present in human cancer, enabling TSG re-expression without DNA demethylation.
  • Transcriptional coactivators are recruited to hypermethylated TSG promoters through MBDs during MeTA.
  • Reactivation of MLH1 by MeTA was associated with histone H3 lysine 9/14 acetylation at the promoter.
  • All ten genes examined across three cell lines showed reactivation due to MeTA.

Conclusions:

  • MeTA provides an efficient mechanism for reactivating epigenetically silenced tumor suppressor genes in cancer.
  • The findings facilitate the identification of transcriptionally silenced genes with methylated CpG islands, including TSGs and crucial developmental genes.
  • MeTA represents a novel epigenetic regulatory pathway with significant implications for cancer therapy and developmental biology research.

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