The roles of <scp>PAD2</scp>‐ and <scp>PAD4</scp>‐mediated protein citrullination catalysis in cancers

Wang, Yanbin; Chen, Riping; Gan, Yihan; Ying, Shibo

doi:10.1002/ijc.33205

Cited by 30 publications

(13 citation statements)

References 78 publications

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“…Wang et al have reviewed the roles of PAD2- and PAD4-mediated protein citrullination in various forms of cancers. These enzymes can have an opposite role, either promoting tumor development or reducing its malignancy, depending on tumor localization and on the pathway affected [ 35 ]. Activated Jurkat cells overexpressing the PAD2 enzyme showed apoptotic features together with an increased citrullination of proteins, including VIM.…”

Section: Resultsmentioning

confidence: 99%

Pediatric Brain Tumors: Signatures from the Intact Proteome

Rossetti

Inserra

Nesticò

et al. 2022

IJMS

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The present investigation aimed to explore the intact proteome of tissues of pediatric brain tumors of different WHO grades and localizations, including medulloblastoma, pilocytic astrocytoma, and glioblastoma, in comparison with the available data on ependymoma, to contribute to the understanding of the molecular mechanisms underlying the onset and progression of these pathologies. Tissues have been homogenized in acidic water–acetonitrile solutions containing proteases inhibitors and analyzed by LC–high resolution MS for proteomic characterization and label-free relative quantitation. Tandem MS spectra have been analyzed by either manual inspection or software elaboration, followed by experimental/theoretical MS fragmentation data comparison by bioinformatic tools. Statistically significant differences in protein/peptide levels between the different tumor histotypes have been evaluated by ANOVA test and Tukey’s post-hoc test, considering a p-value > 0.05 as significant. Together with intact protein and peptide chains, in the range of molecular mass of 1.3–22.8 kDa, several naturally occurring fragments from major proteins, peptides, and proteoforms have been also identified, some exhibiting proper biological activities. Protein and peptide sequencing allowed for the identification of different post-translational modifications, with acetylations, oxidations, citrullinations, deamidations, and C-terminal truncations being the most frequently characterized. C-terminal truncations, lacking from two to four amino acid residues, particularly characterizing the β-thymosin peptides and ubiquitin, showed a different modulation in the diverse tumors studied. With respect to the other tumors, medulloblastoma, the most frequent malignant brain tumor of the pediatric age, was characterized by higher levels of thymosin β4 and β10 peptides, the latter and its des-IS form particularly marking this histotype. The distribution pattern of the C-terminal truncated forms was also different in glioblastoma, particularly underlying gender differences, according to the definition of male and female glioblastoma as biologically distinct diseases. Glioblastoma was also distinguished for the peculiar identification of the truncated form of the α-hemoglobin chain, lacking the C-terminal arginine, and exhibiting oxygen-binding and vasoconstrictive properties different from the intact form. The proteomic characterization of the undigested proteome, following the top-down approach, was challenging to originally investigate the post-translational events that differently characterize pediatric brain tumors. This study provides a contribution to elucidate the molecular profiles of the solid tumors most frequently affecting the pediatric age, and which are characterized by different grades of aggressiveness and localization.

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Section: Resultsmentioning

confidence: 99%

Pediatric Brain Tumors: Signatures from the Intact Proteome

Rossetti

Inserra

Nesticò

et al. 2022

IJMS

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“…Other studies used H3cit as a marker of NETs in tissues either solitary or in combination with other markers [18,19,25,33]. However, in solid tumours, arginine deimination (also referred to as citrullination) of histones has also been observed during epigenetic regulation of gene expression [34]. In agreement with this, PAD4 (the enzyme catalysing histone H3 citrullination) was reported to be frequently overexpressed in cancer cells [35].…”

Section: Nets Induce Motility and Epithelial-mesenchymal Transition (...mentioning

confidence: 88%

Neutrophil extracellular traps drive epithelial–mesenchymal transition of human colon cancer

Stehr

Wang

Demmler

et al. 2022

The Journal of Pathology

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Neutrophil extracellular traps (NETs) are extracellular structures, composed of nuclear DNA and various proteins released from neutrophils. Evidence is growing that NETs exert manifold functions in infection, immunity and cancer. Recently, NETs have been detected in colorectal cancer (CRC) tissues, but their association with disease progression and putative functional impact on tumourigenesis remained elusive. Using high-resolution stimulated emission depletion (STED) microscopy, we showed that citrullinated histone H3 (H3cit) is sufficient to specifically detect citrullinated NETs in colon cancer tissues. Among other evidence, this was supported by the close association of H3cit with de-condensed extracellular DNA, the hallmark of NETs. Extracellular DNA was reliably differentiated from nuclear condensed DNA by staining with an anti-DNA antibody, providing a novel and valuable tool to detect NETs in formalin-fixed paraffin-embedded tissues. Using these markers, the clinical association of NETs was investigated in a cohort of 85 patients with colon cancer. NETs were frequently detected (37/85, 44%) in colon cancer tissue sections and preferentially localised either only in the tumour centre or both in the tumour centre and the invasive front. Of note, citrullinated NETs were significantly associated with high histopathological tumour grades and lymph node metastasis. In vitro, purified NETs induced filopodia formation and cell motility in CRC cell lines. This was associated with increased expression of mesenchymal marker mRNAs (vimentin [VIM], fibronectin [FN1]) and epithelialmesenchymal transition promoting transcription factors (ZEB1, Slug [SNAI2]), as well as decreased expression of the epithelial markers E-cadherin (CDH1) and epithelial cell adhesion molecule (EPCAM). These findings indicated that NETs activate an epithelial-mesenchymal transition-like process in CRC cells and may contribute to the metastatic progression of CRC.

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“… 1255 When PAD2 is inhibited, the expression of ACSL4 and baculovirus‐containing IAP repeats is reduced in the breast cancer cell line MCF‐7. 1256 Abnormal expression of these genes is related to dysregulated lipid metabolism and tumor cell invasion. 1257 …”

Section: Citrullinationmentioning

confidence: 99%

“… 1277 PAD inhibitors may also prevent the expression of genes related to cancer cell invasion and metastasis. 1256 …”

Section: Citrullinationmentioning

confidence: 99%

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Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

Zhong

Xiao

Xie

et al. 2023

MedComm

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Protein posttranslational modifications (PTMs) refer to the breaking or generation of covalent bonds on the backbones or amino acid side chains of proteins and expand the diversity of proteins, which provides the basis for the emergence of organismal complexity. To date, more than 650 types of protein modifications, such as the most well‐known phosphorylation, ubiquitination, glycosylation, methylation, SUMOylation, short‐chain and long‐chain acylation modifications, redox modifications, and irreversible modifications, have been described, and the inventory is still increasing. By changing the protein conformation, localization, activity, stability, charges, and interactions with other biomolecules, PTMs ultimately alter the phenotypes and biological processes of cells. The homeostasis of protein modifications is important to human health. Abnormal PTMs may cause changes in protein properties and loss of protein functions, which are closely related to the occurrence and development of various diseases. In this review, we systematically introduce the characteristics, regulatory mechanisms, and functions of various PTMs in health and diseases. In addition, the therapeutic prospects in various diseases by targeting PTMs and associated regulatory enzymes are also summarized. This work will deepen the understanding of protein modifications in health and diseases and promote the discovery of diagnostic and prognostic markers and drug targets for diseases.

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The roles of PAD2‐ and PAD4‐mediated protein citrullination catalysis in cancers

Cited by 30 publications

References 78 publications

Pediatric Brain Tumors: Signatures from the Intact Proteome

Pediatric Brain Tumors: Signatures from the Intact Proteome

Neutrophil extracellular traps drive epithelial–mesenchymal transition of human colon cancer

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

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