Synergistic activation of functional estrogen receptor (ER)-α by DNA methyltransferase and histone deacetylase inhibition in human ER-α-negative breast cancer cells

X. Yang, D. L. Phillips, A. T. Ferguson, William G Nelson, J. G. Herman, N. E. Davidson

Research output: Contribution to journalArticle

Abstract

Formation of transcriptional repression complexes such as DNA methyltransferase (DNMT) 1/histone deacetylase (HDAC) or methyl-CpG binding protein/HDAC is emerging as an important mechanism in silencing a variety of methylated tissue-specific and imprinted genes. Our previous studies showed that treatment of estrogen receptor (ER)-α-negative human breast cancer cells with the DNMT inhibitor 5-aza-2′-deoxycytidine (5-aza-dC) led to ER mRNA and protein re-expression. Also, the HDAC inhibitor trichostatin A (TSA) could induce ER transcript about 5-fold. Here we show that 5-aza-dC alone induced ER transcript about 30-40-fold, and the addition of TSA elevated ER mRNA expression about 10-fold more in the human ER-negative breast cancer cell lines MDA-MB-231 and MDA-MB-435. Overall, the combination of 5-aza-dC and TSA induced a 300-400-fold increase in ER transcript. Restoration of estrogen responsiveness was demonstrated by the ability of the induced ER protein to elicit estrogen response element-regulated reporter activity from an exogenous plasmid as well as induce expression of the ER target gene, progesterone receptor. The synergistic activation of ER occurs concomitantly with markedly reduced soluble DNMT1 expression and activity, partial demethylation of the ER CpG island, and increased acetylation of histones H3and H4. These data suggest that the activities of both DNMT1 and HDAC are key regulators of methylation-mediated ER gene silencing.

Original languageEnglish (US)
Pages (from-to)7025-7029
Number of pages5
JournalCancer Research
Volume61
Issue number19
StatePublished - Oct 1 2001

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Histone Deacetylases
Methyltransferases
Estrogen Receptors
Breast Neoplasms
decitabine
DNA
trichostatin A
Estrogens
Histone Deacetylase 1
Messenger RNA
CpG Islands
Histone Deacetylase Inhibitors
Response Elements
Gene Silencing
Progesterone Receptors
Acetylation
Histones
Methylation
Genes
Carrier Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Synergistic activation of functional estrogen receptor (ER)-α by DNA methyltransferase and histone deacetylase inhibition in human ER-α-negative breast cancer cells. / Yang, X.; Phillips, D. L.; Ferguson, A. T.; Nelson, William G; Herman, J. G.; Davidson, N. E.

In: Cancer Research, Vol. 61, No. 19, 01.10.2001, p. 7025-7029.

Research output: Contribution to journalArticle

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