Citrullination in Cancer

Abstract

Posttranslational modifications of proteins have been implicated in pathogenesis of numerous diseases. Arginine deimination (also known as citrullination) has a principal role in progression of rheumatoid arthritis through generation of autoantibodies and exacerbation of the inflammatory response. Recently, multiple research groups provided solid evidence of citrullination being in control of cancer progression; however, there is no comprehensive overview of these findings. This article summarizes and critically reviews the influence of citrul-lination on different aspects of tumor biology, including (i) regulation of apoptosis and differentiation, (ii) promoting EMT and metastasis, and (iii) potential use of citrullinated antigens for immunotherapy. In addition, (iv) the role of citrullination as a cancer biomarker and (v) implication of neutrophil extracellular traps in tumorigenesis are discussed. In summary, current findings testify to the significance of arginine deimination in tumor biology and thus more basic and translational studies are needed to further explore this topic. Brief Overview of PAD Biology and Function in Physiologic ConditionsPADs are a group of five Ca 2þ -dependent enzymes (PAD1-4 and PAD6), sharing 70% to 95% sequence homology and expressed in a wide range of tissues and organs ( Fig. 1D;

Ependymoma Pediatric Brain Tumor Protein Fingerprinting by Integrated Mass Spectrometry Platforms: A Pilot Investigation

“…The citrullination PTM of GFAP and vimentin, reported as due to the action of the Protein-arginine deiminase type-2 (PAD2) enzyme in brain tissue [35,36], produces the loss of charge of the arginine residue, resulting in longer chromatographic retention time (see Figure 1 as an example) of the modified peptide due to its increased hydrophobicity. This PTM alters the folding and the biological function of the protein, and it is reportedly involved in the pathogenesis of autoimmune diseases, inflammation, tumor biology, and progression [37,38]. To the best of our knowledge, the detection of citrullinated GFAP and vimentin peptides has not been reported in pediatric brain tumor tissues.…”

Post-Translational Protein Deimination Signatures in Serum and Serum-Extracellular Vesicles of Bos taurus Reveal Immune, Anti-Pathogenic, Anti-Viral, Metabolic and Cancer-Related Pathways for Deimination

“…Bovine leukemia virus has furthermore been linked to telomerase upregulation and tumor induction in cattle [230]. PADs and deimination have been widely studied in a range of cancers, including via epigenetic regulation [9][10][11]100,[231][232][233][234] but this is the first identification of post-translational regulation of such pathways via deimination in cattle.…”

Peptidyl Arginine Deiminase 2 (PADI2)-Mediated Arginine Citrullination Modulates Transcription in Cancer

“…Despite the high homology among family members, the five PADI enzymes have definite features, which facilitates the regulation of several distinct cellular processes. This feature may explain why altered levels of citrullination are associated with different pathological conditions, including multiple cancers [4,15,[35][36][37][38][39][40][41]. Remarkably, PADI2 and PADI4 had distinct as well as overlapping substrates, for example, PADI4 directly citrullinates nuclear factor κB (NF-κB) p65 to promote its nuclear localization and transcriptional activity of key immune genes including IL-1β and tumor necrosis factor α (TNFα) to propagates inflammation in rheumatoid arthritis [42], whereas, mice with TNFα-induced inflammatory arthritis showed that PADI2 contributes to TNFα-induced citrullination, but not required for NETosis.…”