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. 2012:2012:895343.
doi: 10.1155/2012/895343. Epub 2012 Sep 16.

Potential role of peptidylarginine deiminase enzymes and protein citrullination in cancer pathogenesis

Sunish Mohanan  1 , Brian D Cherrington, Sachi Horibata, John L McElwee, Paul R Thompson, Scott A Coonrod
Affiliations

Potential role of peptidylarginine deiminase enzymes and protein citrullination in cancer pathogenesis

Sunish Mohanan et al. Biochem Res Int. 2012.

Abstract

The peptidylarginine deiminases (PADs) are a family of posttranslational modification enzymes that catalyze the conversion of positively charged protein-bound arginine and methylarginine residues to the uncharged, nonstandard amino acid citrulline. This enzymatic activity is referred to as citrullination or, alternatively, deimination. Citrullination can significantly affect biochemical pathways by altering the structure and function of target proteins. Five mammalian PAD family members (PADs 1-4 and 6) have been described and show tissue-specific distribution. Recent reviews on PADs have focused on their role in autoimmune diseases. Here, we will discuss the potential role of PADs in tumor progression and tumor-associated inflammation. In the context of cancer, increasing clinical evidence suggests that PAD4 (and possibly PAD2) has important roles in tumor progression. The link between PADs and cancer is strengthened by recent findings showing that treatment of cell lines and mice with PAD inhibitors significantly suppresses tumor growth and, interestingly, inflammatory symptoms. At the molecular level, transcription factors, coregulators, and histones are functional targets for citrullination by PADs, and citrullination of these targets can affect gene expression in multiple tumor cell lines. Next generation isozyme-specific PAD inhibitors may have therapeutic potential to regulate both the inflammatory tumor microenvironment and tumor cell growth.

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Figures

Figure 1
Figure 1
Peptidylarginine deiminase (PAD) enzymes catalyze the conversion of protein arginine residues to citrulline.
Figure 2
Figure 2
PAD-mediated histone tail citrullination leads to chromatin decondensation.
Figure 3
Figure 3
H4cit3 immunostaining of DCIS xenograft sections. Dotted line demarcates the area adjacent to the central necrotic core of the comedo-DCIS lesion. (Magnification 400x).
Figure 4
Figure 4
PAD2 IHC staining of the normal human mammary gland, a DCIS lesion, and invasive carcinomas. Nuclear staining intensity is reduced in most invasive tumors while a subset of these tumors retains strong PAD2 staining. (Magnification 200x).
Figure 5
Figure 5
PAD2 (green) is expressed in luminal epithelial cells of preinvasive, invasive, and metastatic human mammary tumors. Cytokeratin (red) staining differentiates luminal epithelial type from myoepithelial cells. (Magnification 400x).
Figure 6
Figure 6
PAD inhibitors and their selectivity (TDFA-Threonine-aspartate-F-amidine; TDCA-Threonine-aspartate-Cl-amidine).
Figure 7
Figure 7
Potential role of PAD enzymes in cancer pathogenesis.
See this image and copyright information in PMC

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