The Burden of Post-Translational Modification (PTM)—Disrupting Mutations in the Tumor Matrisome

Holstein, Elisa; Dittmann, Annalena; Kääriäinen, Anni; Pesola, Vilma; Koivunen, Jarkko; Pihlajaniemi, Taina; Naba, Alexandra; Izzi, Valerio

doi:10.3390/cancers13051081

Cited by 16 publications

(14 citation statements)

References 89 publications

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“…The 3D and 2D structures of interaction between the proposed receptors and top-ranked drug molecules were constructed and visualized using USCF Chimera program and Discovery Studio Visualizer 2021 software ( Pettersen et al, 2004 ). Then, we validated the selected drug molecules with the cancer-related post-translational modification (PTM) sites (phosphorylation, ubiquitination, and succinylation) through docking analysis ( Hasan et al, 2016 ; Wang et al, 2020 ; Holstein et al, 2021 ; Mu et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Gene expression profile analysis to discover molecular signatures for early diagnosis and therapies of triple-negative breast cancer

Alam

Sultana

Wang

et al. 2022

Front. Mol. Biosci.

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Triple-negative breast cancer (TNBC) is one of the most lethal subtypes of breast cancer (BC), and it accounts for approximately 10%–20% of all invasive BCs diagnosed worldwide. The survival rate of TNBC in stages III and IV is very low, and a large number of patients are diagnosed in these stages. Therefore, the purpose of this study was to identify TNBC-causing molecular signatures and anti-TNBC drug agents for early diagnosis and therapies. Five microarray datasets that contained 304 TNBC and 109 control samples were collected from the Gene Expression Omnibus (GEO) database, and RNA-Seq data with 116 tumor and 124 normal samples were collected from TCGA database to identify differentially expressed genes (DEGs) between TNBC and control samples. A total of 64 DEGs were identified, of which 29 were upregulated and 35 were downregulated, by using the statistical limma R-package. Among them, seven key genes (KGs) were commonly selected from microarray and RNA-Seq data based on the high degree of connectivity through PPI (protein–protein interaction) and module analysis. Out of these seven KGs, six KGs (TOP2A, BIRC5, AURKB, ACTB, ASPM, and BUB1B) were upregulated and one (EGFR) was downregulated. We also investigated their differential expression patterns with different subtypes and progression stages of BC by the independent datasets of RNA-seq profiles from UALCAN database, which indicated that they may be potential biomarkers for early diagnosis. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses with the proposed DEGs were performed using the online Enrichr database to investigate the pathogenetic processes of TNBC highlighting KGs. Then, we performed gene regulatory network analysis and identified three transcriptional (SOX2, E2F4, and KDM5B) and three post-transcriptional (hsa-mir-1-3p, hsa-mir-124-3p, and hsa-mir-34a-5p) regulators of KGs. Finally, we proposed five KG-guided repurposable drug molecules (imatinib, regorafenib, pazopanib, teniposide, and dexrazoxane) for TNBC through network pharmacology and molecular docking analyses. These drug molecules also showed significant binding performance with some cancer-related PTM-sites (phosphorylation, succinylation, and ubiquitination) of top-ranked four key proteins (EGFR, AURKB, BIRC5, and TOP2A). Therefore, the findings of this computational study may play a vital role in early diagnosis and therapies against TNBC by wet-lab validation.

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Section: Methodsmentioning

confidence: 99%

Gene expression profile analysis to discover molecular signatures for early diagnosis and therapies of triple-negative breast cancer

Alam

Sultana

Wang

et al. 2022

Front. Mol. Biosci.

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“…Recently, it has been demonstrated that different types of PTM can be specifically distributed depending on protein functional category or its subcellular localization 24 , which indicates accumulation of type-specific PTMs in certain cancer phenotype and support a clue in tumorigenesis. Similarly, we observed a sensible variation of PTM types across cancer phenotypes in our study (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Proteomic and molecular dynamic investigations of PTM-induced structural fluctuations in breast and ovarian cancer

Тихонов

Kulikova

Kopylov

et al. 2021

Sci Rep

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Post-translational processing leads to conformational changes in protein structure that modulate molecular functions and change the signature of metabolic transformations and immune responses. Some post-translational modifications (PTMs), such as phosphorylation and acetylation, are strongly related to oncogenic processes and malignancy. This study investigated a PTM pattern in patients with gender-specific ovarian or breast cancer. Proteomic profiling and analysis of cancer-specific PTM patterns were performed using high-resolution UPLC-MS/MS. Structural analysis, topology, and stability of PTMs associated with sex-specific cancers were analyzed using molecular dynamics modeling. We identified highly specific PTMs, of which 12 modified peptides from eight distinct proteins derived from patients with ovarian cancer and 6 peptides of three proteins favored patients from the group with breast cancer. We found that all defined PTMs were localized in the compact and stable structural motifs exposed outside the solvent environment. PTMs increase the solvent-accessible surface area of the modified moiety and its active environment. The observed conformational fluctuations are still inadequate to activate the structural degradation and enhance protein elimination/clearance; however, it is sufficient for the significant modulation of protein activity.

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“…Post-translational modification of cancer-associated extracellular matrix (ECM) alters the interaction of cancer cells with its microenvironment and influences malignancy and tumour growth [ 96 ]. Citrullination is produced through post-translational deamination of peptidyl-arginine and is catalysed by peptidylarginine deiminase (PAD).…”

Section: Post-translational Protein Modification In Colorectal Liver ...mentioning

confidence: 99%

Proteomic Profiling and Biomarker Discovery in Colorectal Liver Metastases

Wong

Diakos

Hugh

et al. 2022

IJMS

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Colorectal liver metastases (CRLM) are the leading cause of death among patients with metastatic colorectal cancer (CRC). As part of multimodal therapy, liver resection is the mainstay of curative-intent treatment for select patients with CRLM. However, effective treatment of CRLM remains challenging as recurrence occurs in most patients after liver resection. Proposed clinicopathologic factors for predicting recurrence are inconsistent and lose prognostic significance over time. The rapid development of next-generation sequencing technologies and decreasing DNA sequencing costs have accelerated the genomic profiling of various cancers. The characterisation of genomic alterations in CRC has significantly improved our understanding of its carcinogenesis. However, the functional context at the protein level has not been established for most of this genomic information. Furthermore, genomic alterations do not always result in predicted changes in the corresponding proteins and cancer phenotype, while post-transcriptional and post-translational regulation may alter synthesised protein levels, affecting phenotypes. More recent advancements in mass spectrometry-based technology enable accurate protein quantitation and comprehensive proteomic profiling of cancers. Several studies have explored proteomic biomarkers for predicting CRLM after oncologic resection of primary CRC and recurrence after curative-intent resection of CRLM. The current review aims to rationalise the proteomic complexity of CRC and explore the potential applications of proteomic biomarkers in CRLM.

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The Burden of Post-Translational Modification (PTM)—Disrupting Mutations in the Tumor Matrisome

Cited by 16 publications

References 89 publications

Gene expression profile analysis to discover molecular signatures for early diagnosis and therapies of triple-negative breast cancer

Gene expression profile analysis to discover molecular signatures for early diagnosis and therapies of triple-negative breast cancer

Proteomic and molecular dynamic investigations of PTM-induced structural fluctuations in breast and ovarian cancer

Proteomic Profiling and Biomarker Discovery in Colorectal Liver Metastases

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