Sialylated IgG-activated integrin β4-Src-Erk axis stabilizes c-Myc in a p300 lysine acetyltransferase-dependent manner to promote colorectal cancer liver metastasis
Background: Liver metastasis is a leading cause of colorectal cancer mortality. Therefore, the underlying mechanism and potential therapeutic target of colorectal cancer liver metastasis urge to be found. Mounting evidence indicates that cancer-derived sialylated IgG promotes tumor formation and pro...
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Elsevier
2025-03-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558625000193 |
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| author | Jing Chen Shenghua Zhang Xinmei Huang Qianqian Wang Weiyan Xu Jing Huang Yuming Su Qinkun Sun Xiaojuan Du Baocai Xing Xiaoyan Qiu |
| author_facet | Jing Chen Shenghua Zhang Xinmei Huang Qianqian Wang Weiyan Xu Jing Huang Yuming Su Qinkun Sun Xiaojuan Du Baocai Xing Xiaoyan Qiu |
| author_sort | Jing Chen |
| collection | DOAJ |
| description | Background: Liver metastasis is a leading cause of colorectal cancer mortality. Therefore, the underlying mechanism and potential therapeutic target of colorectal cancer liver metastasis urge to be found. Mounting evidence indicates that cancer-derived sialylated IgG promotes tumor formation and progression. However, the role of sialylated IgG in colorectal cancer liver metastasis remains undefined. Materials and methods: Analysis of sialylated IgG in paired tumor tissues and adjacent normal tissues from 65 colorectal cancer patients was performed using immunohistochemical staining. Functional assays of sialylated IgG were explored in vitro and in vivo. The downstream target of sialylated IgG was investigated by performing gene-set enrichment analysis, ubiquitination assay, cycloheximide chase assay, acetylation assay and co-immunoprecipitation. Results: Here, our investigation reveals that sialylated IgG is significantly upregulated in colorectal cancer and that the increase of IgG is positively associated with liver metastasis and poor overall survival in colorectal cancer patients. Sialylated IgG promotes colorectal cancer cell migration, invasion and liver metastasis. Notably, anti-sialylated IgG antibody effectively blocks colorectal cancer liver metastasis in mouse models. Mechanistically, sialylated IgG upregulates c-Myc protein level by decreasing c-Myc ubiquitination. Moreover, we find that p300/CBP can stabilize c-Myc by reducing c-Myc ubiquitination. Overexpression of p300/CBP protects c-Myc protein level from sialylated IgG-knockdown in a lysine acetyltransferase activity-dependent manner. Furthermore, sialylated IgG upregulates p300 protein level through integrin β4-FAK-Src-Erk signaling. Conclusion: Collectively, these results indicate that a novel sialylated IgG-integrin β4-FAK-Src-Erk-p300-c-Myc signaling pathway promotes colorectal cancer liver metastasis, thus providing potential therapeutic targets for colorectal cancer liver metastasis. |
| format | Article |
| id | doaj-art-acd5d073b67a4b29bf3e1e1e871546ec |
| institution | DOAJ |
| issn | 1476-5586 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj-art-acd5d073b67a4b29bf3e1e1e871546ec2025-08-20T02:55:13ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862025-03-016110114010.1016/j.neo.2025.101140Sialylated IgG-activated integrin β4-Src-Erk axis stabilizes c-Myc in a p300 lysine acetyltransferase-dependent manner to promote colorectal cancer liver metastasisJing Chen0Shenghua Zhang1Xinmei Huang2Qianqian Wang3Weiyan Xu4Jing Huang5Yuming Su6Qinkun Sun7Xiaojuan Du8Baocai Xing9Xiaoyan Qiu10Hepatopancreatobiliary Surgery Department I, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, 100142, ChinaDepartment of Immunology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing, 100191, China; Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, Peking University, Beijing, 100191, ChinaDepartment of Immunology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing, 100191, China; Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, Peking University, Beijing, 100191, ChinaDepartment of Immunology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing, 100191, China; Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, Peking University, Beijing, 100191, ChinaDepartment of Immunology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing, 100191, China; Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, Peking University, Beijing, 100191, ChinaDepartment of Immunology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing, 100191, China; Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, Peking University, Beijing, 100191, ChinaHepatopancreatobiliary Surgery Department I, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, 100142, ChinaDepartment of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, ChinaDepartment of Cell Biology, School of Basic Medical Sciences, Peking University, Beijing, 100083, ChinaHepatopancreatobiliary Surgery Department I, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, 100142, China; Corresponding author at: Hepatopancreatobiliary Surgery Department I, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, 100142, China.Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing, 100191, China; Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, Peking University, Beijing, 100191, China; Corresponding author at: Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.Background: Liver metastasis is a leading cause of colorectal cancer mortality. Therefore, the underlying mechanism and potential therapeutic target of colorectal cancer liver metastasis urge to be found. Mounting evidence indicates that cancer-derived sialylated IgG promotes tumor formation and progression. However, the role of sialylated IgG in colorectal cancer liver metastasis remains undefined. Materials and methods: Analysis of sialylated IgG in paired tumor tissues and adjacent normal tissues from 65 colorectal cancer patients was performed using immunohistochemical staining. Functional assays of sialylated IgG were explored in vitro and in vivo. The downstream target of sialylated IgG was investigated by performing gene-set enrichment analysis, ubiquitination assay, cycloheximide chase assay, acetylation assay and co-immunoprecipitation. Results: Here, our investigation reveals that sialylated IgG is significantly upregulated in colorectal cancer and that the increase of IgG is positively associated with liver metastasis and poor overall survival in colorectal cancer patients. Sialylated IgG promotes colorectal cancer cell migration, invasion and liver metastasis. Notably, anti-sialylated IgG antibody effectively blocks colorectal cancer liver metastasis in mouse models. Mechanistically, sialylated IgG upregulates c-Myc protein level by decreasing c-Myc ubiquitination. Moreover, we find that p300/CBP can stabilize c-Myc by reducing c-Myc ubiquitination. Overexpression of p300/CBP protects c-Myc protein level from sialylated IgG-knockdown in a lysine acetyltransferase activity-dependent manner. Furthermore, sialylated IgG upregulates p300 protein level through integrin β4-FAK-Src-Erk signaling. Conclusion: Collectively, these results indicate that a novel sialylated IgG-integrin β4-FAK-Src-Erk-p300-c-Myc signaling pathway promotes colorectal cancer liver metastasis, thus providing potential therapeutic targets for colorectal cancer liver metastasis.http://www.sciencedirect.com/science/article/pii/S1476558625000193Sialylated IgGColorectal cancer liver metastasisc-Mycp300Erk |
| spellingShingle | Jing Chen Shenghua Zhang Xinmei Huang Qianqian Wang Weiyan Xu Jing Huang Yuming Su Qinkun Sun Xiaojuan Du Baocai Xing Xiaoyan Qiu Sialylated IgG-activated integrin β4-Src-Erk axis stabilizes c-Myc in a p300 lysine acetyltransferase-dependent manner to promote colorectal cancer liver metastasis Neoplasia: An International Journal for Oncology Research Sialylated IgG Colorectal cancer liver metastasis c-Myc p300 Erk |
| title | Sialylated IgG-activated integrin β4-Src-Erk axis stabilizes c-Myc in a p300 lysine acetyltransferase-dependent manner to promote colorectal cancer liver metastasis |
| title_full | Sialylated IgG-activated integrin β4-Src-Erk axis stabilizes c-Myc in a p300 lysine acetyltransferase-dependent manner to promote colorectal cancer liver metastasis |
| title_fullStr | Sialylated IgG-activated integrin β4-Src-Erk axis stabilizes c-Myc in a p300 lysine acetyltransferase-dependent manner to promote colorectal cancer liver metastasis |
| title_full_unstemmed | Sialylated IgG-activated integrin β4-Src-Erk axis stabilizes c-Myc in a p300 lysine acetyltransferase-dependent manner to promote colorectal cancer liver metastasis |
| title_short | Sialylated IgG-activated integrin β4-Src-Erk axis stabilizes c-Myc in a p300 lysine acetyltransferase-dependent manner to promote colorectal cancer liver metastasis |
| title_sort | sialylated igg activated integrin β4 src erk axis stabilizes c myc in a p300 lysine acetyltransferase dependent manner to promote colorectal cancer liver metastasis |
| topic | Sialylated IgG Colorectal cancer liver metastasis c-Myc p300 Erk |
| url | http://www.sciencedirect.com/science/article/pii/S1476558625000193 |
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