Investigating the expression, effect and tumorigenic pathway of PADI2 in tumors

Guo, Wei; Zheng, Yabing; Xu, Bing; Ma, Fengwang; Li, Chang; Zhang, Xiaoqian; Wang, Yao; Chang, Xiaotian

doi:10.2147/ott.s92389

Cited by 38 publications

(50 citation statements)

References 23 publications

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“…Many elongation factors and kinases are implicated in the control of RNAP2 transcription pause release, a mechanism that controls the expression of genes involved in cancer progression and metastasis, like CDK9, c-MYC, and JMJD6 Bywater et al, 2013;Miller et al, 2017). PADI2 is also found overexpressed in breast cancer and other cancers (Guo et al, 2017). Indeed, we found that PADI2 depletion or mutation of R1810 reduced cell proliferation of breast cancer cells by modulating cell cycle progression.…”

Section: Discussionmentioning

confidence: 65%

Arginine Citrullination at the C-Terminal Domain Controls RNA Polymerase II Transcription

et al. 2019

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Graphical AbstractHighlights d PADI2 citrullinates arginine1810 (cit1810) at CTD of RNA polymerase II (RNAP2) d PADI2 and R1810 regulate transcription and proliferation of breast cancer cells d Absence of cit1810 leads to RNAP2 accumulation at proximal promoter regions d Cit1810 facilitates interaction of RNAP2 with P-TEFb complex SUMMARYThe post-translational modification of key residues at the C-terminal domain of RNA polymerase II (RNAP2-CTD) coordinates transcription, splicing, and RNA processing by modulating its capacity to act as a landing platform for a variety of protein complexes.Here, we identify a new modification at the CTD, the deimination of arginine and its conversion to citrulline by peptidyl arginine deiminase 2 (PADI2), an enzyme that has been associated with several diseases, including cancer. We show that, among PADI family members, only PADI2 citrullinates R1810 (Cit1810) at repeat 31 of the CTD. Depletion of PADI2 or loss of R1810 results in accumulation of RNAP2 at transcription start sites, reduced gene expression, and inhibition of cell proliferation. Cit1810 is needed for interaction with the P-TEFb (positive transcription elongation factor b) kinase complex and for its recruitment to chromatin. In this way, CTD-Cit1810 favors RNAP2 pause release and efficient transcription in breast cancer cells.

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Section: Discussionmentioning

confidence: 65%

Arginine Citrullination at the C-Terminal Domain Controls RNA Polymerase II Transcription

et al. 2019

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“…They catalyze the process of citrullination modification of proteins [42]. When the process is upregulated, it would disturb the stability of proteins and caused DNA damages, which is associated with carcinogenesis involved in the stomach, the liver, the large intestine, oral squamous cell carcinoma and so on [42][43][44]. Interestingly, overexpression of PADI driven by MZF1 and Sp1/Sp3 binding to the promoter region can citrullinate PKM2 and stimulate glycolysis in cancer cells [45,46].…”

Section: Discussionmentioning

confidence: 99%

Construction of a novel gene-based model for prognosis prediction of clear cell renal cell carcinoma

et al. 2020

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Background: Clear cell renal cell carcinoma (ccRCC) comprises the majority of kidney cancer death worldwide, whose incidence and mortality are not promising. Identifying ideal biomarkers to construct a more accurate prognostic model than conventional clinical parameters is crucial.Methods: Raw count of RNA-sequencing data and clinicopathological data were acquired from The Cancer Genome Atlas (TCGA). Tumor samples were divided into two sets. Differentially expressed genes (DEGs) were screened in the whole set and prognosis-related genes were identified from the training set. Their common genes were used in LASSO and best subset regression which were performed to identify the best prognostic 5 genes. The gene-based risk score was developed based on the Cox coefficient of the individual gene. Time-dependent receiver operating characteristic (ROC) and Kaplan-Meier (KM) survival analysis were used to assess its prognostic power. GSE29609 dataset from GEO (Gene Expression Omnibus) database was used to validate the signature. Univariate and multivariate Cox regression were performed to screen independent prognostic parameters to construct a nomogram. The predictive power of the nomogram was revealed by time-dependent ROC curves and the calibration plot and verified in the validation set. Finally, Functional enrichment analysis of DEGs and 5 novel genes were performed to suggest the potential biological pathways.Results: PADI1, ATP6V0D2, DPP6, C9orf135 and PLG were screened to be significantly related to the prognosis of ccRCC patients. The risk score effectively stratified the patients into high-risk group with poor overall survival (OS) based on survival analysis. AJCC-stage, age, recurrence and risk score were regarded as independent prognostic parameters by Cox regression analysis and were used to construct a nomogram. Time-dependent ROC curves showed the nomogram performed best in 1-, 3-and 5-year survival predictions compared with AJCC-stage and risk score in validation sets. The calibration plot showed good agreement of the nomogram between predicted and observed outcomes. Functional enrichment analysis suggested several enriched biological pathways related to cancer. Conclusions:In our study, we constructed a gene-based model integrating clinical prognostic parameters to predict prognosis of ccRCC well, which might provide a reliable prognosis assessment tool for clinician and aid treatment decision-making in the clinic. © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article' s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article'

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“…However, the expression of PADI2 has been characterized in non‐uterine cancers. Compared to normal tissue, PADI2 protein is increased in breast, cervical, colon, liver, lung, ovarian serous, thyroid, 20 and prostate cancers 21 . PADI2 mRNA expression is upregulated in tamoxifen‐resistant 22 and HER2/ERBB2 + breast cancers 23 .…”

Section: Discussionmentioning

confidence: 99%

Proteomic profiling of FBXW7‐mutant serous endometrial cancer cells reveals upregulation of PADI2, a potential therapeutic target

Urick

Bell

2020

Cancer Medicine

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Background:Despite advancements over the past decade revealing molecular aberrations characteristic of endometrial cancer (EC) subtypes, serous ECs remain difficult to treat and associated with poor outcomes. This is due, in part, to the rarity of these tumors within clinical trials and the inability to directly target the most frequent genomic abnormalities. One of the most commonly somatically mutated genes in serous ECs is the tumor suppressor F-box and WD repeat domain containing 7 (FBXW7). Methods: To identify changes in protein expression associated with FBXW7 mutation, we clustered regularly interspaced short palindromic repeats (CRISPR)-edited ARK4 FBXW7 nonmutant serous EC cells to insert recurrent FBXW7 mutations. We then compared the liquid chromatography tandem mass spectrometry-based proteomic profiles of CRISPR-edited ARK1 and ARK4 serous EC cells to matched parental cells. Results: Among distinct total and phosphorylated proteins that were significantly differentially expressed in FBXW7-mutant cell lines compared to matched parental lines, we identified increased PADI2 (peptidyl arginine deiminase 2) expression in all ARK1 and ARK4 CRISPR-edited FBXW7-mutant cell lines. We further confirmed the correlation between FBXW7 mutation and increased PADI2 expression in a third biological background, JHUEM-1 endometrioid EC cells. Finally, we established that PADI2 protein is expressed in primary serous endometrial tumors. Conclusion: Our findings provide novel insight into proteomic changes associated with FBXW7 mutation in serous ECs and identify PADI2 as a novel potential therapeutic target for these tumors.

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Investigating the expression, effect and tumorigenic pathway of PADI2 in tumors

Cited by 38 publications

References 23 publications

Arginine Citrullination at the C-Terminal Domain Controls RNA Polymerase II Transcription

Arginine Citrullination at the C-Terminal Domain Controls RNA Polymerase II Transcription

Construction of a novel gene-based model for prognosis prediction of clear cell renal cell carcinoma

Proteomic profiling of FBXW7‐mutant serous endometrial cancer cells reveals upregulation of PADI2, a potential therapeutic target

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