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.
Highlights
peptidylarginine deiminases (PADs)-mediated citrullination can alter the tertiary structure of target substrates and/or alter protein-protein interactions; affecting various cellular processes [1, 2] (Figure 1)
This study showed that the ERαdependent increase in PAD4 expression can be mediated by estrogen signaling to the PAD4 proximal promoter via cross-talk with the AP-1, Sp-1, and NF-Y transcription factors [47]
Protein citrullination is emerging as a critical posttranslational modification in developmental biology, inflammation, and cancer pathogenesis
Summary
PAD-mediated citrullination can alter the tertiary structure of target substrates and/or alter protein-protein interactions; affecting various cellular processes [1, 2] (Figure 1). Protein citrullination has garnered increased attention due to its role in the pathogenesis of various inflammatory conditions such as rheumatoid arthritis (RA), multiple sclerosis, psoriasis, chronic obstructive pulmonary disease (COPD), neurodegenerative diseases and, due to its emerging role in various human and animal cancers [3,4,5,6,7]. We will first briefly discuss the tissue-specificity and hormonal regulation of the five PAD isoforms and focus on the potential role of this enzyme family in carcinogenesis, tumor progression, and inflammation
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