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

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date


Document Type



Amidines; Animals; Antibiotics, Antineoplastic; Antigens, CD38; Antineoplastic Agents; Cell Differentiation; Cell Line, Tumor; Cell Survival; Cyclin-Dependent Kinase Inhibitor p21; Doxorubicin; Drug Synergism; Enzyme Inhibitors; Epigenomics; Gene Expression Regulation, Neoplastic; Humans; Hydrolases; Neoplasms


Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Neoplasms | Therapeutics


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

DOI of Published Version



Cell Mol Life Sci. 2011 Feb;68(4):709-20. doi: 10.1007/s00018-010-0480-x. Link to article on publisher's site. Epub 2010 Aug 13.

Journal/Book/Conference Title

Cellular and molecular life sciences : CMLS


At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.

Related Resources

Link to Article in PubMed