Histone deacetylase inhibitor LBH589 reactivates silenced estrogen receptor alpha (ER) gene expression without loss of DNA hypermethylation

Qun Zhou, Peter Atadja, Nancy E. Davidson

Research output: Contribution to journalArticle

Abstract

Our previous studies demonstrated that inhibition of histone deacetylases (HDACs) by trichostatin A reactivates estrogen receptor alpha (ER) gene expression in ER-negative breast cancer cells. Here, we use the clinically relevant HDAC inhibitor, LBH589 (LBH) to explore the roles of HDAC in ER gene silencing. In the ER-negative human breast cancer lines, MDA-MB-231 and MDA-MB-435, treatment with LBH for 24 hours restored ER mRNA and protein expression without a concomitant demethylation of the CpG island at the ER promoter. The expression of ER mRNA was sustained at least 96 hours after withdrawal of LBH treatment. Restoration of ER expression by LBH enhanced 4-hydroxytamoxifen sensitivity in MDA-MB-231 cells. The molecular mechanisms by which LBH reactivated silenced ER gene in MDA-MB-231 cells were examined with emphasis on chromatin structure reorganization. By chromatin immunoprecipitation analysis, LBH treatment released DNMT1, HDAC1, and the H3 lysine 9 (H3-K9) methyltransferase SUV39H1 from the ER promoter. Such changes were associated with an active chromatin formation manifested as accumulation of acetylated histones H3 and H4, a decrease in methylated H3-K9, and an impaired binding of heterochromatin protein 1 (HP1α) at the promoter. Our findings suggest that HDAC inhibitors could restore expression of the silenced ER gene by reorganizing the heterochromatin-associated proteins without alteration in promoter DNA hypermethylation.

Original languageEnglish (US)
Pages (from-to)64-69
Number of pages6
JournalCancer Biology and Therapy
Volume6
Issue number1
StatePublished - Jan 2007

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Histone Deacetylase Inhibitors
Estrogen Receptor alpha
Gene Expression
DNA
Histone Deacetylases
Histones
Chromatin
trichostatin A
panobinostat
Breast Neoplasms
Messenger RNA
CpG Islands
Heterochromatin
Chromatin Immunoprecipitation
Methyltransferases
Gene Silencing
Genes
Lysine
Carrier Proteins

Keywords

  • DNA methylation
  • DNMT1
  • DNMT3A/3B
  • H3
  • H3 K9 methylation
  • H4
  • HDAC
  • HP1
  • Silenced ER
  • SUV39H1

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Histone deacetylase inhibitor LBH589 reactivates silenced estrogen receptor alpha (ER) gene expression without loss of DNA hypermethylation. / Zhou, Qun; Atadja, Peter; Davidson, Nancy E.

In: Cancer Biology and Therapy, Vol. 6, No. 1, 01.2007, p. 64-69.

Research output: Contribution to journalArticle

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