Protein arginine deiminase 4: a target for an epigenetic cancer therapy
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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.
KeywordsProtein arginine deiminase Haloacetamidine Inhibition HL-60 Epigenetics Citrulline
Protein Arginine Deiminase
All trans retinoic acid
Retinoic acid receptor
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.
- 18.Leatherbarrow RJ (2004) Grafit Ver 5.0. Erathicus Software, StainesGoogle Scholar
- 32.Wilson AJ, Byun DS, Popova N, Murray LB, L’Italien K, Sowa Y, Arango D, Velcich A, Augenlicht LH, Mariadason JM (2006) Histone deacetylase 3 (HDAC3) and other class I HDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer. J Biol Chem 281:13548–13558CrossRefPubMedGoogle Scholar