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Cytosolic TGM2 promotes malignant progression in gastric cancer by suppressing the TRIM21‐mediated ubiquitination/degradation of STAT1 in a GTP binding‐dependent modality
BACKGROUND: Previous studies have revealed the critical role of transglutaminase 2 (TGM2) as a potential therapeutic target in cancers, but the oncogenic roles and underlying mechanisms of TGM2 in gastric cancer (GC) are not fully understood. In this study, we examined the role and potential mechani...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9859732/ https://www.ncbi.nlm.nih.gov/pubmed/36353796 http://dx.doi.org/10.1002/cac2.12386 |
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author | Zhang, Lu Li, Qingya Yang, Jing Xu, Penghui Xuan, Zhe Xu, Jianghao Xu, Zekuan |
author_facet | Zhang, Lu Li, Qingya Yang, Jing Xu, Penghui Xuan, Zhe Xu, Jianghao Xu, Zekuan |
author_sort | Zhang, Lu |
collection | PubMed |
description | BACKGROUND: Previous studies have revealed the critical role of transglutaminase 2 (TGM2) as a potential therapeutic target in cancers, but the oncogenic roles and underlying mechanisms of TGM2 in gastric cancer (GC) are not fully understood. In this study, we examined the role and potential mechanism of TGM2 in GC. METHODS: Western blotting, immunohistochemistry, CCK8, colony formation and transwell assays were used to measure TGM2 expression in the GC cells and tissues and to examine the in vitro role of TGM2 in GC. Xenograft and in vivo metastasis experiments were performed to examine the in vivo role of TGM2 in GC. Gene set enrichment analysis, quantitative PCR and western blotting were conducted to screen for potential TGM2 targets involved in GC. Gain/loss‐of‐function and rescue experiments were conducted to detect the biological roles of STAT1 in GC cells in the context of TGM2. Co‐immunoprecipitation, mass spectrometry, quantitative PCR and western blotting were conducted to identify STAT1‐interacting proteins and elucidate their regulatory mechanisms. Mutations in TGM2 and two molecules (ZM39923 and A23187) were used to identify the enzymatic activity of TGM2 involved in the malignant progression of GC and elucidate the underlying mechanism. RESULTS: In this study, we demonstrated elevated TGM2 expression in the GC tissues, which closely related to pathological grade, and predicted poor survival in patients with GC. TGM2 overexpression or knockdown promoted (and inhibited) cell proliferation, migration, and invasion, which were reversed by STAT1 knockdown or overexpression. Further studies showed that TGM2 promoted GC progression by inhibiting STAT1 ubiquitination/degradation. Then, tripartite motif‐containing protein 21 (TRIM21) was identified as a ubiquitin E3 ligase of STAT1 in GC. TGM2 maintained STAT1 stability by facilitating the dissociation of TRIM21 and STAT1 with GTP‐binding enzymatic activity. A23187 abolished the role of TGM2 in STAT1 and reversed the pro‐tumor role of TGM2 in vitro and in vivo. CONCLUSIONS: This study revealed a critical role and regulatory mechanism of TGM2 on STAT1 in GC and highlighted the potential of TGM2 as a therapeutic target, which elucidates the development of medicine or strategies by regulating the GTP‐binding activity of TGM2 in GC. |
format | Online Article Text |
id | pubmed-9859732 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-98597322023-01-24 Cytosolic TGM2 promotes malignant progression in gastric cancer by suppressing the TRIM21‐mediated ubiquitination/degradation of STAT1 in a GTP binding‐dependent modality Zhang, Lu Li, Qingya Yang, Jing Xu, Penghui Xuan, Zhe Xu, Jianghao Xu, Zekuan Cancer Commun (Lond) Original Articles BACKGROUND: Previous studies have revealed the critical role of transglutaminase 2 (TGM2) as a potential therapeutic target in cancers, but the oncogenic roles and underlying mechanisms of TGM2 in gastric cancer (GC) are not fully understood. In this study, we examined the role and potential mechanism of TGM2 in GC. METHODS: Western blotting, immunohistochemistry, CCK8, colony formation and transwell assays were used to measure TGM2 expression in the GC cells and tissues and to examine the in vitro role of TGM2 in GC. Xenograft and in vivo metastasis experiments were performed to examine the in vivo role of TGM2 in GC. Gene set enrichment analysis, quantitative PCR and western blotting were conducted to screen for potential TGM2 targets involved in GC. Gain/loss‐of‐function and rescue experiments were conducted to detect the biological roles of STAT1 in GC cells in the context of TGM2. Co‐immunoprecipitation, mass spectrometry, quantitative PCR and western blotting were conducted to identify STAT1‐interacting proteins and elucidate their regulatory mechanisms. Mutations in TGM2 and two molecules (ZM39923 and A23187) were used to identify the enzymatic activity of TGM2 involved in the malignant progression of GC and elucidate the underlying mechanism. RESULTS: In this study, we demonstrated elevated TGM2 expression in the GC tissues, which closely related to pathological grade, and predicted poor survival in patients with GC. TGM2 overexpression or knockdown promoted (and inhibited) cell proliferation, migration, and invasion, which were reversed by STAT1 knockdown or overexpression. Further studies showed that TGM2 promoted GC progression by inhibiting STAT1 ubiquitination/degradation. Then, tripartite motif‐containing protein 21 (TRIM21) was identified as a ubiquitin E3 ligase of STAT1 in GC. TGM2 maintained STAT1 stability by facilitating the dissociation of TRIM21 and STAT1 with GTP‐binding enzymatic activity. A23187 abolished the role of TGM2 in STAT1 and reversed the pro‐tumor role of TGM2 in vitro and in vivo. CONCLUSIONS: This study revealed a critical role and regulatory mechanism of TGM2 on STAT1 in GC and highlighted the potential of TGM2 as a therapeutic target, which elucidates the development of medicine or strategies by regulating the GTP‐binding activity of TGM2 in GC. John Wiley and Sons Inc. 2022-11-09 /pmc/articles/PMC9859732/ /pubmed/36353796 http://dx.doi.org/10.1002/cac2.12386 Text en © 2022 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat‐sen University Cancer Center. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Articles Zhang, Lu Li, Qingya Yang, Jing Xu, Penghui Xuan, Zhe Xu, Jianghao Xu, Zekuan Cytosolic TGM2 promotes malignant progression in gastric cancer by suppressing the TRIM21‐mediated ubiquitination/degradation of STAT1 in a GTP binding‐dependent modality |
title | Cytosolic TGM2 promotes malignant progression in gastric cancer by suppressing the TRIM21‐mediated ubiquitination/degradation of STAT1 in a GTP binding‐dependent modality |
title_full | Cytosolic TGM2 promotes malignant progression in gastric cancer by suppressing the TRIM21‐mediated ubiquitination/degradation of STAT1 in a GTP binding‐dependent modality |
title_fullStr | Cytosolic TGM2 promotes malignant progression in gastric cancer by suppressing the TRIM21‐mediated ubiquitination/degradation of STAT1 in a GTP binding‐dependent modality |
title_full_unstemmed | Cytosolic TGM2 promotes malignant progression in gastric cancer by suppressing the TRIM21‐mediated ubiquitination/degradation of STAT1 in a GTP binding‐dependent modality |
title_short | Cytosolic TGM2 promotes malignant progression in gastric cancer by suppressing the TRIM21‐mediated ubiquitination/degradation of STAT1 in a GTP binding‐dependent modality |
title_sort | cytosolic tgm2 promotes malignant progression in gastric cancer by suppressing the trim21‐mediated ubiquitination/degradation of stat1 in a gtp binding‐dependent modality |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9859732/ https://www.ncbi.nlm.nih.gov/pubmed/36353796 http://dx.doi.org/10.1002/cac2.12386 |
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