Cellular and Molecular Life Sciences

, Volume 68, Issue 4, pp 709–720

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

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

DOI: 10.1007/s00018-010-0480-x

Cite this article as:
Slack, J.L., Causey, C.P. & Thompson, P.R. Cell. Mol. Life Sci. (2011) 68: 709. doi:10.1007/s00018-010-0480-x


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.


Protein arginine deiminase Haloacetamidine Inhibition HL-60 Epigenetics Citrulline 



Protein Arginine Deiminase


Histone deacetylase


Rheumatoid arthritis


Estrogen receptor


Thyroid receptor


All trans retinoic acid


Retinoic acid receptor

Supplementary material

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

Copyright information

© Springer Basel AG 2010

Authors and Affiliations

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