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Genomic DNA hypomethylation by histone deacetylase inhibition implicates DNMT1 nuclear dynamics

Mohsen Karimi Arzenani1, Atosa Esteki Zade, Yu Ming

  • 1Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Hospital, SE-171 76 Stockholm, Sweden.

Molecular and Cellular Biology
|July 28, 2011
PubMed

Insights

Histone deacetylase inhibitors like trichostatin A reduce DNA methylation and alter DNA methyltransferase 1 (DNMT1) dynamics, offering insights into combined cancer therapies.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Molecular Pharmacology

Background:

  • Histone deacetylase inhibitors (HDACi) reactivate silenced tumor suppressor genes, showing antitumor potential.
  • Combined HDACi and DNA methylation inhibitor (DNMTi) therapy is a promising cancer treatment strategy.
  • Synergistic effects of combined therapies may involve common targets like DNA methyltransferase 1 (DNMT1).

Purpose of the Study:

  • To investigate the effect of trichostatin A (HDACi) on DNA methylation and DNMT1 nuclear dynamics.
  • To elucidate the molecular mechanisms underlying the interaction between HDACi and DNMTi.

Main Methods:

  • Utilized single-molecule sensitive methods: confocal laser scanning microscopy with avalanche photodiode detectors (APD imaging).
  • Employed fluorescence correlation spectroscopy (FCS) to study DNMT1 nuclear dynamics in live cells.
  • Assessed global and gene-specific DNA methylation changes following trichostatin A treatment.

Main Results:

  • Trichostatin A treatment decreased global DNA methylation levels.
  • Observed a reduction in DNMT1 protein levels after trichostatin A administration.
  • Demonstrated altered nuclear dynamics and chromatin interactions of DNMT1.

Conclusions:

  • HDACi trichostatin A impacts DNA methylation and DNMT1 behavior through mechanisms distinct from DNMT inhibitors like 5-azacytidine.
  • Findings illuminate molecular mechanisms of HDACi and DNMTi synergy.
  • Results may inform improved cancer treatment strategies involving combined epigenetic therapies.

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