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

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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.

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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

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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.

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, SC, 29208, USA

    Jessica L. Slack, Corey P. Causey & Paul R. Thompson

  2. Department of Chemistry, The Scripps Research Institute, Scripps Florida, 120 Scripps Way, Jupiter, FL, 33458, USA

    Jessica L. Slack & Paul R. Thompson

Authors
  1. Jessica L. Slack
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  2. Corey P. Causey
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Correspondence to Paul R. Thompson.

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Slack, J.L., Causey, C.P. & Thompson, P.R. Protein arginine deiminase 4: a target for an epigenetic cancer therapy. Cell. Mol. Life Sci. 68, 709–720 (2011). https://doi.org/10.1007/s00018-010-0480-x

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  • DOI: https://doi.org/10.1007/s00018-010-0480-x

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