Histone citrullination: a new target for tumors

Zhu, Dongwei; Zhang, Yue; Wang, Shengjun

doi:10.1186/s12943-021-01373-z

Cited by 69 publications

(68 citation statements)

References 166 publications

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“…Studies in cancer cell lines demonstrated that the occurrence of histone citrullination, mediated by PAD4, on p53-regulated genes, including p21, CIP1, WAF1 and OKL38 repressed their transcriptional activation, leading to cell cycle arrest and apoptosis [ 158 , 159 ]. These findings are in support of the notion that targeting PAD4 and other PAD enzymes may provide a novel strategy to inhibit tumor growth [ 160 ]. Immunohistochemistry and western blot detection demonstrated PAD4 overexpression in various tumor types, especially adenocarcinoma.…”

Section: Protein Citrullination As a Hallmark Of Immune Disorderssupporting

confidence: 84%

Citrullination in the pathology of inflammatory and autoimmune disorders: recent advances and future perspectives

Ciesielski

Biesiekierska

Panthu

et al. 2022

Cell. Mol. Life Sci.

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Numerous post-translational modifications (PTMs) govern the collective metabolism of a cell through altering the structure and functions of proteins. The action of the most prevalent PTMs, encompassing phosphorylation, methylation, acylations, ubiquitination and glycosylation is well documented. A less explored protein PTM, conversion of peptidylarginine to citrulline, is the subject of this review. The process of citrullination is catalysed by peptidylarginine deiminases (PADs), a family of conserved enzymes expressed in a variety of human tissues. Accumulating evidence suggest that citrullination plays a significant role in regulating cellular metabolism and gene expression by affecting a multitude of pathways and modulating the chromatin status. Here, we will discuss the biochemical nature of arginine citrullination, the enzymatic machinery behind it and also provide information on the pathological consequences of citrullination in the development of inflammatory diseases (rheumatoid arthritis, multiple sclerosis, psoriasis, systemic lupus erythematosus, periodontitis and COVID-19), cancer and thromboembolism. Finally, developments on inhibitors against protein citrullination and recent clinical trials providing a promising therapeutic approach to inflammatory disease by targeting citrullination are discussed.

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Section: Protein Citrullination As a Hallmark Of Immune Disorderssupporting

confidence: 84%

Citrullination in the pathology of inflammatory and autoimmune disorders: recent advances and future perspectives

Ciesielski

Biesiekierska

Panthu

et al. 2022

Cell. Mol. Life Sci.

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“…With respect to the role of citrullination in the oral mucosa, Arita et al reported that PAD contributes to the integrity of the stratum corneum of the oral mucosa by citrullinating filaggrin and profilaggrin in the rat palate [ 32 ]. In addition to filaggrin, other citrullinated peptides with physiological roles include the glial cell fibrillary acidic protein [ 33 ], myelin basic protein [ 34 ], and histones [ 35 ]. For example, physiologically, citrullinated vimentin causes intermediate filament proteins to lose their ability to polymerize and form filaments [ 36 ], and citrullinated histones are involved in the regulation of gene expression and neutrophil extracellular trap formation.…”

Section: Discussionmentioning

confidence: 99%

Detection of salivary citrullinated cytokeratin 13 in healthy individuals and patients with rheumatoid arthritis by proteomics analysis

2022

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The immune response to citrullinated peptides in the mucosa has been suggested to play an important role in the transition from pre-onset rheumatoid arthritis (RA) to clinically evident RA. Although there are reports indicating the presence of anti-citrullinated peptide antibodies in the saliva, few studies have reported citrullinated peptide detection in human saliva. This study aimed to identify citrullinated peptides in human saliva and discuss their clinical significance. Saliva samples were collected from 11 patients with RA and from 20 healthy individuals. Citrullinated peptides were detected using an anti-modified citrulline (AMC) antibody. Saliva from the healthy individuals was subjected to two-dimensional protein electrophoresis to isolate citrullinated peptides, which were analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and mass spectrometry by peptide mass fingerprinting. The results were corroborated by immunoprecipitation (IP)-western blotting. The signal intensities of the bands precipitated with anti-cytokeratin 13 (CK13) and AMC antibodies were quantified. The signal intensity ratio of the band produced by the AMC antibody was divided by that of the band produced by the anti-CK13 antibody to calculate the citrullinated CK13 (Cit-CK13) ratio. A citrullinated peptide band corresponding to a molecular weight of approximately 50 kDa was detected in the saliva of healthy individuals, and identified as CK13 via mass spectrometry and IP-western blotting. No significant difference was observed between the salivary Cit-CK13 ratios of patients with RA and healthy participants (p = 0.605). This is the first study to show that Cit-CK13 is present in human saliva, and that there is no significant difference between the Cit-CK13 ratios of patients with RA and healthy individuals, suggesting that salivary Cit-CK13 content and RA development may not be associated. The physiological and pathological roles of Cit-CK13 in the oral cavity, and its responsiveness to mucosal immunity, remain unknown and will be the subject of further investigation.

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“…With respect to histone deimination, while only PAD4 has a classical nuclear translocation signal, both PAD2 and PAD3 are also reported with nuclear location and found to deiminate histones [ 11 , 16 , 17 , 31 , 33 ]. Histone citrullination is strongly associated to tumours [ 54 ] and CitH3 is a common marker for NETosis, which has also been used as an indicative marker for cancer-associated inflammatory processes. For example, such processes have been associated with awakening dormant cancer cells [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

A Pilot Study on Peptidylarginine Deiminases and Protein Deimination in Animal Cancers across Vertebrate Species

Inal

Hristova²,

Lange

2022

IJMS

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PADs are a group of calcium-dependent enzymes that play key roles in inflammatory pathologies and have diverse roles in cancers. PADs cause irreversible post-translational modification of arginine to citrulline, leading to changes in protein function in different cellular compartments. PAD isozyme diversity differs throughout phylogeny in chordates, with five PAD isozymes in mammals, three in birds, and one in fish. While the roles for PADs in various human cancers are mounting (both in regards to cancer progression and epigenetic regulation), investigations into animal cancers are scarce. The current pilot-study therefore aimed at assessing PAD isozymes in a range of animal cancers across the phylogeny tree. In addition, the tissue samples were assessed for total protein deimination and histone H3 deimination (CitH3), which is strongly associated with human cancers and also indicative of gene regulatory changes and neutrophil extracellular trap formation (NETosis). Cancers were selected from a range of vertebrate species: horse, cow, reindeer, sheep, pig, dog, cat, rabbit, mink, hamster, parrot, and duck. The cancers chosen included lymphoma, kidney, lung, testicular, neuroendocrine, anaplastic, papilloma, and granulosa cell tumour. Immunohistochemical analysis revealed that CitH3 was strongly detected in all of the cancers assessed, while pan-deimination detection was overall low. Both PAD2 and PAD3 were the most predominantly expressed PADs across all of the cancers assessed, while PAD1, PAD4, and PAD6 were overall expressed at lower, albeit varying, levels. The findings from this pilot study provide novel insights into PAD-mediated roles in different cancers across a range of vertebrate species and may aid in the understanding of cancer heterogeneity and cancer evolution.

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Histone citrullination: a new target for tumors

Cited by 69 publications

References 166 publications

Citrullination in the pathology of inflammatory and autoimmune disorders: recent advances and future perspectives

Citrullination in the pathology of inflammatory and autoimmune disorders: recent advances and future perspectives

Detection of salivary citrullinated cytokeratin 13 in healthy individuals and patients with rheumatoid arthritis by proteomics analysis

A Pilot Study on Peptidylarginine Deiminases and Protein Deimination in Animal Cancers across Vertebrate Species

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