Transglutaminase 6 Is Colocalized and Interacts with Mutant Huntingtin in Huntington Disease Rodent Animal Models

Schulze-Krebs, Anja; Canneva, Fabio; Stemick, Judith; Plank, Anne-Christine; Harrer, Julia; Bates, Gillian P.; Aeschlimann, Daniel; Steffan, Joan S.; Hörsten, Stephan von

doi:10.3390/ijms22168914

Cited by 7 publications

(5 citation statements)

References 89 publications

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“…Mutation, CNV and DNA methylation analysis of TG family members TG mutations have been demonstrated to related to various diseases (20,(39)(40)(41). Mutations of TG family genes were also identi ed in TCGA cohort (Fig.…”

Section: Results Expression Patterns and Clinical Relevances Of Tgs I...mentioning

confidence: 88%

Transglutaminases are oncogenic biomarkers in human cancers and therapeutic targeting of TGM2 blocks chemoresistance and macrophage infiltration in pancreatic cancer

Zhang

Yao

et al. 2023

Cell Oncol.

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Backgroud:Transglutaminases (TGs) are multifunctional enzymes with transglutaminase cross-linking, atypical GTPase/ATPase and kinase activity. Here, an integrated comprehensive analysis shows the genomic, transcriptomic and immunological landscapes of the TGs varies among different cancers. MethodsGene expression pattern and immune cell in ltration in pan-cancer were obtained from The Cancer Genome Atlas (TCGA) databases and Gene Set Enrichment Analysis (GSEA) datasets. Western blotting, immuno uorescence, ELISA, and orthotopic xenograft model were performed to validate our databasederived results. ResultsThe overall expression of TGs (designated as TG score) is signi cantly upregulated in multiple cancers and related to worse patient survial. The expression of the TG family can be regulated by multiple mechanisms at the genetic, epigenetic and transcriptional levels. Transcriptionfactors crucial for epithelial to mesenchymal transition (EMT) are commonly correlated with TG score in many cancer types.Importantly, TGM2 expression displays a close connection with the chemoresistances of a wide range of chemodrugs. TGM2, F13A1 and overall TG score are positively correlated with the in ltration of immune cells in all cancer types tested. Functional and clinical veri cation reveals that higher TGM2 expression is linked with worse patient survival, increased IC 50 value of gemcitabine, and abundant tumor-in ltrating macrophages in pancreatic cancer. Mechanistically, increased C-C motif chemokine ligand 2 (CCL2) release affored by TGM2 contributes to macrophage in ltration with tumor microenvironment. ConclusionsThese results reveal the relevances and molecular networks of TG genes in human cancers, highlighting the signi cance of TGM2 in pancreatic cancer which may provide some promising directions for immunotherapy and dealing with chemoresistance.

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Section: Results Expression Patterns and Clinical Relevances Of Tgs I...mentioning

confidence: 88%

Transglutaminases are oncogenic biomarkers in human cancers and therapeutic targeting of TGM2 blocks chemoresistance and macrophage infiltration in pancreatic cancer

Zhang

Yao

et al. 2023

Cell Oncol.

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show abstract

Section: Results Expression Patterns and Clinical Relevances Of Tgs I...mentioning

confidence: 90%

Transglutaminases are oncogenic biomarkers in human cancers and therapeutic targeting of TGM2 blocks chemoresistance and macrophage infiltration in pancreatic cancer

Zhang

Yao

et al. 2023

Preprint

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Backgroud: Transglutaminases (TGs) are multifunctional enzymes with transglutaminase cross-linking, atypical GTPase/ATPase and kinase activity. Here, an integrated comprehensive analysis shows the genomic, transcriptomic and immunological landscapes of the TGs varies among different cancers. Methods Gene expression pattern and immune cell infiltration in pan-cancer were obtained from The Cancer Genome Atlas (TCGA) databases and Gene Set Enrichment Analysis (GSEA) datasets. Western blotting, immunofluorescence, ELISA, and orthotopic xenograft model were performed to validate our database-derived results. Results The overall expression of TGs (designated as TG score) is significantly upregulated in multiple cancers and related to worse patient survial. The expression of the TG family can be regulated by multiple mechanisms at the genetic, epigenetic and transcriptional levels. Transcriptionfactors crucial for epithelial to mesenchymal transition (EMT) are commonly correlated with TG score in many cancer types. Importantly, TGM2 expression displays a close connection with the chemoresistances of a wide range of chemodrugs. TGM2, F13A1 and overall TG score are positively correlated with the infiltration of immune cells in all cancer types tested. Functional and clinical verification reveals that higher TGM2 expression is linked with worse patient survival, increased IC50 value of gemcitabine, and abundant tumor-infiltrating macrophages in pancreatic cancer. Mechanistically, increased C-C motif chemokine ligand 2 (CCL2) release affored by TGM2 contributes to macrophage infiltration with tumor microenvironment. Conclusions These results reveal the relevances and molecular networks of TG genes in human cancers, highlighting the significance of TGM2 in pancreatic cancer which may provide some promising directions for immunotherapy and dealing with chemoresistance.

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“…Moreover, studies in cellular and drosophila models have shown that TG2 acts as a selective corepressor of the nuclear genes involved in HD, whereas the inhibition of its activity or the prevention of its translocation to the nucleus fails to repress transcription [97]. In addition to TG2, TG6 physically interacts with mHTT and contributes to mHTT aggregates in HD transgenic animals, highlighting the role of TG6 activity in the pathogenesis of HD [168].…”

Section: Tg2 In Huntington's Diseasementioning

confidence: 99%

Pathogenetic Contributions and Therapeutic Implications of Transglutaminase 2 in Neurodegenerative Diseases

Liu,

Mouradian

2024

IJMS

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Neurodegenerative diseases encompass a heterogeneous group of disorders that afflict millions of people worldwide. Characteristic protein aggregates are histopathological hallmark features of these disorders, including Amyloid β (Aβ)-containing plaques and tau-containing neurofibrillary tangles in Alzheimer’s disease, α-Synuclein (α-Syn)-containing Lewy bodies and Lewy neurites in Parkinson’s disease and dementia with Lewy bodies, and mutant huntingtin (mHTT) in nuclear inclusions in Huntington’s disease. These various aggregates are found in specific brain regions that are impacted by neurodegeneration and associated with clinical manifestations. Transglutaminase (TG2) (also known as tissue transglutaminase) is the most ubiquitously expressed member of the transglutaminase family with protein crosslinking activity. To date, Aβ, tau, α-Syn, and mHTT have been determined to be substrates of TG2, leading to their aggregation and implicating the involvement of TG2 in several pathophysiological events in neurodegenerative disorders. In this review, we summarize the biochemistry and physiologic functions of TG2 and describe recent advances in the pathogenetic role of TG2 in these diseases. We also review TG2 inhibitors tested in clinical trials and discuss recent TG2-targeting approaches, which offer new perspectives for the design of future highly potent and selective drugs with improved brain delivery as a disease-modifying treatment for neurodegenerative disorders.

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Transglutaminase 6 Is Colocalized and Interacts with Mutant Huntingtin in Huntington Disease Rodent Animal Models

Cited by 7 publications

References 89 publications

Transglutaminases are oncogenic biomarkers in human cancers and therapeutic targeting of TGM2 blocks chemoresistance and macrophage infiltration in pancreatic cancer

Transglutaminases are oncogenic biomarkers in human cancers and therapeutic targeting of TGM2 blocks chemoresistance and macrophage infiltration in pancreatic cancer

Transglutaminases are oncogenic biomarkers in human cancers and therapeutic targeting of TGM2 blocks chemoresistance and macrophage infiltration in pancreatic cancer

Pathogenetic Contributions and Therapeutic Implications of Transglutaminase 2 in Neurodegenerative Diseases

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