Trichostatin A and 5 Aza-2' deoxycytidine decrease estrogen receptor mRNA stability in ER positive MCF7 cells through modulation of HuR

Breast Cancer Res Treat. 2008 Sep;111(1):15-25. doi: 10.1007/s10549-007-9751-0. Epub 2007 Sep 21.


Trichostatin A (TSA) and 5-Aza 2'deoxycytidine (AZA), two well characterized pharmacologic inhibitors of histone deacetylation and DNA methylation, affect estrogen receptor alpha (ER) levels differently in ER-positive versus ER-negative breast cancer cell lines. Whereas pharmacologic inhibition of these epigenetic mechanisms results in re-expression and increased estrogen receptor alpha (ER) levels in ER-negative cells, treatment in ER-positive MCF7 cells results in decreased ER mRNA and protein levels. This decrease is dependent upon protein interaction with the ER 3'UTR. Actinomycin D studies showed a 37.5% reduction in ER mRNA stability from 4 to 1.5 h in AZA/TSA treated MCF7 cell lines; an effect not seen in 231ER + cells transfected with the ER coding region but lacking incorporation of the 3'UTR. AZA/TSA do not appear to directly interact with the 3'UTR but rather decrease stability through altered subcellular localization of the RNA binding protein, HuR. siRNA inhibition of HuR expression reduces both the steady-state and stability of ER mRNA, suggesting that HuR plays a critical role in the control of ER mRNA stability. Our data suggest that epigenetic modulators can alter stability through modulation of HuR subcellular distribution. Taken together, these data provide a novel anti-estrogenic mechanism for AZA and TSA in ER positive human breast cancer cells.

MeSH terms

  • 3' Untranslated Regions / genetics
  • Antigens, Surface / drug effects*
  • Antigens, Surface / metabolism
  • Azacitidine / analogs & derivatives*
  • Azacitidine / pharmacology
  • Base Sequence
  • Blotting, Western
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Decitabine
  • ELAV Proteins
  • ELAV-Like Protein 1
  • Enzyme Inhibitors / pharmacology
  • Epigenesis, Genetic
  • Estrogen Receptor Modulators / pharmacology*
  • Estrogen Receptor alpha / drug effects*
  • Estrogen Receptor alpha / genetics
  • Female
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Immunoprecipitation
  • Molecular Sequence Data
  • Oligonucleotide Array Sequence Analysis
  • RNA Stability / drug effects
  • RNA, Messenger / drug effects
  • RNA-Binding Proteins / drug effects*
  • RNA-Binding Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transfection


  • 3' Untranslated Regions
  • Antigens, Surface
  • ELAV Proteins
  • ELAV-Like Protein 1
  • ELAVL1 protein, human
  • Enzyme Inhibitors
  • Estrogen Receptor Modulators
  • Estrogen Receptor alpha
  • Hydroxamic Acids
  • RNA, Messenger
  • RNA-Binding Proteins
  • trichostatin A
  • Decitabine
  • Azacitidine