Breast Cancer Research and Treatment

, Volume 111, Issue 1, pp 15–25 | Cite as

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

  • Peter Pryzbylkowski
  • Oluwakemi Obajimi
  • Judith Clancy Keen
Preclinical Study
First Online:
Received:
Accepted:

Abstract

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.

Keywords

5-Aza-2′deoxycytidine Actinomycin D Breast cancer Estrogen receptor alpha HuR MCF7 mRNA stability Trichostatin A 

Abbreviations

UTR

3′Untranslated region

AZA

5-Aza 2′deoxycytidine

ARE

AU-rich element

ER

Estrogen receptor alpha

HDAC

Histone deacetylase

RBP

RNA binding protein

siRNA

Small interfering RNA

TSA

Trichostatin

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Notes

Acknowledgments

The authors would like to thank Ben Ho Park and Kelly M Mack for their critical evaluation of the manuscript and discussions regarding this project.

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Copyright information

© Springer Science+Business Media, LLC. 2007

Authors and Affiliations

  • Peter Pryzbylkowski
    • 1
  • Oluwakemi Obajimi
    • 1
  • Judith Clancy Keen
    • 1
  1. 1.Department of Medicine, Division of Molecular MedicineRobert Wood Johnson Medical School, University of Medicine and Dentistry of New JerseyCamdenUSA

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