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Cellular and Molecular Life Sciences

, Volume 68, Issue 4, pp 709–720 | Cite as

Protein arginine deiminase 4: a target for an epigenetic cancer therapy

  • Jessica L. Slack
  • Corey P. Causey
  • Paul R. ThompsonEmail author
Research Article

Abstract

The recent approvals of anticancer therapeutic agents targeting the histone deacetylases and DNA methyltransferases have highlighted the important role that epigenetics plays in human diseases, and suggested that the factors controlling gene expression are novel drug targets. Protein arginine deiminase 4 (PAD4) is one such target because its effects on gene expression parallel those observed for the histone deacetylases. We demonstrated that F- and Cl-amidine, two potent PAD4 inhibitors, display micromolar cytotoxic effects towards several cancerous cell lines (HL-60, MCF7 and HT-29); no effect was observed in noncancerous lines (NIH 3T3 and HL-60 granulocytes). These compounds also induced the differentiation of HL-60 and HT29 cells. Finally, these compounds synergistically potentiated the cell killing effects of doxorubicin. Taken together, these findings suggest PAD4 inhibition as a novel epigenetic approach for the treatment of cancer, and suggest that F- and Cl-amidine are candidate therapeutic agents for this disease.

Keywords

Protein arginine deiminase Haloacetamidine Inhibition HL-60 Epigenetics Citrulline 

Abbreviations

PAD

Protein Arginine Deiminase

HDAC

Histone deacetylase

RA

Rheumatoid arthritis

ER

Estrogen receptor

TR

Thyroid receptor

ATRA

All trans retinoic acid

RAR

Retinoic acid receptor

Notes

Acknowledgments

We thank Hening Lin and Hong Jiang for the generous gift of Rh-6(F-araNAD), and Michael Wyatt, Franklin Berger and Lee Ferguson, respectively, for the generous gifts of the HT-29, NIH3T3, and MCF7 cells. We also thank Franklin Berger for providing critical comments on the manuscript. This work was supported by NIH grant GM079357 to PRT.

Conflicts of interest

The authors declare a conflict of interest. The University of South Carolina and P.R.T have a financial interest in F-amidine and Cl-amidine.

Supplementary material

18_2010_480_MOESM1_ESM.pdf (217 kb)
Supplementary material 1 (PDF 217 kb)

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Copyright information

© Springer Basel AG 2010

Authors and Affiliations

  • Jessica L. Slack
    • 1
    • 2
  • Corey P. Causey
    • 1
  • Paul R. Thompson
    • 1
    • 2
    Email author
  1. 1.Department of Chemistry and BiochemistryUniversity of South CarolinaColumbiaUSA
  2. 2.Department of ChemistryThe Scripps Research Institute, Scripps FloridaJupiterUSA

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