Histone deacetylase inhibitors decrease DNA methyltransferase-3B messenger RNA stability and down-regulate De novo DNA methyltransferase activity in human endometrial cells

Yuning Xiong, Sean Christopher Dowdy, Karl C. Podratz, Fan Jin, John R. Attewell, Norman L. Eberhardt, Shi Wen Jiang

Research output: Contribution to journalArticle

126 Citations (Scopus)

Abstract

It is well known that the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) acts synergistically with the DNA methyltransferase (DNMT) inhibitor 5-aza-2′-deoxycytidine (ADC) to reactivate DNA methylation-silenced genes. Moreover, in several studies, TSA was capable of inducing DNA demethylation even in the absence of ADC. Here we describe a mechanism by which HDAC inhibitors affect DNA methylation through their regulation on DNMT3B, a methyltransferase responsible for de novo DNA methylation. Using quantitative real-time PCR and Western blot analysis, we show that TSA down-regulates DNMT3B mRNA and protein expression in human endometrial cancer cells. This decrease in DNMT3B mRNA results in a significant reduction in de novo methylation activities. Further experiments indicated that TSA decreases DNMT3B mRNA stability and reduces its half-life from ∼4 to 2.5 hours. We established that protein synthesis is required for posttranscriptional regulation, suggesting the involvement of an RNase and/or key mRNA stabilization factor(s) controlling the DNMT3B mRNA stability. Therefore, TSA may not only modify histone acetylation, but also potentially alter DNA methylation. Since the HDAC inhibitors are frequently used in epigenetic studies and are considered to be promising anticancer drugs, these new findings will have implications in both laboratory and clinical settings.

Original languageEnglish (US)
Pages (from-to)2684-2689
Number of pages6
JournalCancer Research
Volume65
Issue number7
DOIs
StatePublished - Apr 1 2005

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trichostatin A
Histone Deacetylase Inhibitors
RNA Stability
Methyltransferases
Human Activities
DNA Methylation
Down-Regulation
Messenger RNA
DNA
decitabine
Deoxycytidine
Acetylation
Endometrial Neoplasms
Ribonucleases
Epigenomics
Histones
Methylation
Half-Life
Real-Time Polymerase Chain Reaction
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Histone deacetylase inhibitors decrease DNA methyltransferase-3B messenger RNA stability and down-regulate De novo DNA methyltransferase activity in human endometrial cells. / Xiong, Yuning; Dowdy, Sean Christopher; Podratz, Karl C.; Jin, Fan; Attewell, John R.; Eberhardt, Norman L.; Jiang, Shi Wen.

In: Cancer Research, Vol. 65, No. 7, 01.04.2005, p. 2684-2689.

Research output: Contribution to journalArticle

Xiong, Yuning ; Dowdy, Sean Christopher ; Podratz, Karl C. ; Jin, Fan ; Attewell, John R. ; Eberhardt, Norman L. ; Jiang, Shi Wen. / Histone deacetylase inhibitors decrease DNA methyltransferase-3B messenger RNA stability and down-regulate De novo DNA methyltransferase activity in human endometrial cells. In: Cancer Research. 2005 ; Vol. 65, No. 7. pp. 2684-2689.
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