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Histone deacetylase inhibitors decrease DNA methyltransferase-3B messenger RNA stability and down-regulate de novo
Yuning Xiong1, Sean C Dowdy, Karl C Podratz
1Department of Obstetrics and Gynecology, Division of Endocrinology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Cancer Research
|April 5, 2005
Summary
Histone deacetylase (HDAC) inhibitor trichostatin A (TSA) reduces DNA methyltransferase 3B (DNMT3B) expression and de novo DNA methylation. This epigenetic regulation by TSA offers new insights for cancer therapy.
Area of Science:
- Epigenetics
- Molecular Biology
- Cancer Research
Background:
- Histone deacetylase (HDAC) inhibitors like trichostatin A (TSA) are known to reactivate silenced genes, often synergistically with DNA methyltransferase (DNMT) inhibitors.
- TSA has demonstrated the ability to induce DNA demethylation independently of DNMT inhibitors in prior studies.
- Understanding the precise mechanisms by which HDAC inhibitors influence DNA methylation is crucial for their therapeutic application.
Purpose of the Study:
- To elucidate the mechanism by which HDAC inhibitors, specifically TSA, impact DNA methylation.
- To investigate the effect of TSA on DNMT3B, a key enzyme in de novo DNA methylation.
- To determine the implications of TSA-mediated DNMT3B regulation in human endometrial cancer cells.
Main Methods:
- Quantitative real-time PCR and Western blot analysis were employed to assess DNMT3B mRNA and protein levels.
- De novo methylation activity was measured following TSA treatment.
- mRNA stability assays were conducted to determine the half-life of DNMT3B mRNA.
Main Results:
- TSA significantly down-regulates both DNMT3B mRNA and protein expression in human endometrial cancer cells.
- The observed decrease in DNMT3B leads to a substantial reduction in de novo DNA methylation.
- TSA treatment destabilizes DNMT3B mRNA, reducing its half-life from approximately 4 hours to 2.5 hours, indicating posttranscriptional regulation.
Conclusions:
- HDAC inhibitors like TSA can directly influence DNA methylation by down-regulating DNMT3B expression and activity.
- TSA's effect on DNMT3B mRNA stability suggests a posttranscriptional regulatory mechanism involving protein synthesis, RNases, or mRNA stabilization factors.
- These findings highlight a dual epigenetic action of TSA, affecting both histone acetylation and DNA methylation, with significant implications for epigenetic research and anticancer drug development.