Potential Role of Peptidylarginine Deiminase Enzymes and Protein Citrullination in Cancer Pathogenesis

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.

Citrullination – small change with a great consequence

“…PAD overexpression and changes in their subcellular localization is often accompanied by certain types of cancer (Mohanan et al 2012). Increased levels of PAD4 and its activity is presented in invasive carcinomas like lung adenocarcinomas, esophageal carcinomas with squamous differentiation, colorectal adenocarcinomas and bladder uterine carcinomas etc.…”

“…In the normal breast tissues PAD2 is localized in both the cytoplasm and the nucleus. Changing the location of nuclear PAD2 in certain types of cancer may cause changes in gene expression and cause malignant transformation (Mohanan et al 2012). …”

Peptidylarginine Deiminases as Mediators of Microvesicular Release - Novel Therapeutic Interventions

“…Peptidylarginine deiminases (PADs) are a family of tissue specific calcium activated enzymes that cause irreversible changes of protein-bound arginines into citrullines ( Figure 1a) [20,21], resulting in protein misfolding and functional changes in target proteins ( Figure 1b) [21][22][23]. Both cellular EV release and PAD-mediated protein deimination are calcium-dependent events that are elevated in a number of human diseases including cancer, autoimmunity and neurodegenerative diseases [10,[24][25][26][27][28][29][30][31]. Addressing the putative interplay between PADs and EV biogenesis, we demonstrated in a recent prostate cancer study that PAD enzyme activation plays a functional role in EV biogenesis through deimination of cytoskeletal actins and nuclear histones [7].…”

Inhibiting Protein Arginine Deiminases Has Antioxidant Consequences

“…PAD-mediated citrullination post-translationally modifies target proteins, which affects their function (Vossenaar et al, 2003). Recently, protein citrullination has received increased attention because of its role in the pathogenesis of various inflammatory conditions, such as rheumatoid arthritis, multiple sclerosis, psoriasis, chronic obstructive pulmonary disease, neurodegenerative diseases and, because of its emerging role in various human and animal cancers (Mohanan et al, 2012). Biochemical and genetic evidence suggests that dysregulated PADs also contribute to the onset and progression of colitis and colon cancer.…”