Integrative proteomics reveals the role of E3 ubiquitin ligase SYVN1 in hepatocellular carcinoma metastasis
Abstract Background Tumor metastasis is a major factor for poor prognosis of hepatocellular carcinoma (HCC), but the relationship between ubiquitination and metastasis need to be studied more systematically. We analyzed the ubiquitinome of HCC in this study to have a more comprehensive insight into...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-10-01
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| Series: | Cancer Communications |
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| Online Access: | https://doi.org/10.1002/cac2.12192 |
| _version_ | 1818738172397355008 |
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| author | Feiyang Ji Menghao Zhou Zeyu Sun Zhengyi Jiang Huihui Zhu Zhongyang Xie Xiaoxi Ouyang Lingjian Zhang Lanjuan Li |
| author_facet | Feiyang Ji Menghao Zhou Zeyu Sun Zhengyi Jiang Huihui Zhu Zhongyang Xie Xiaoxi Ouyang Lingjian Zhang Lanjuan Li |
| author_sort | Feiyang Ji |
| collection | DOAJ |
| description | Abstract Background Tumor metastasis is a major factor for poor prognosis of hepatocellular carcinoma (HCC), but the relationship between ubiquitination and metastasis need to be studied more systematically. We analyzed the ubiquitinome of HCC in this study to have a more comprehensive insight into human HCC metastasis. Methods The protein ubiquitination levels in 15 HCC specimens with vascular invasion and 15 without vascular invasion were detected by ubiquitinome. Proteins with significantly different ubiquitination levels between HCCs with and without vascular invasion were used to predict E3 ubiquitin ligases associated with tumor metastasis. The topological network of protein substrates and corresponding E3 ubiquitin ligases was constructed to identify the key E3 ubiquitin ligase. Besides, the growth, migration and invasion ability of LM3 and HUH7 hepatoma cell lines with and without SYVN1 expression interference were measured by cell proliferation assay, subcutaneous tumor assay, umphal vein endothelium tube formation assay, transwell migration and invasion assays. Finally, the interacting proteins of SYVN1 were screened and verified by protein interaction omics, immunofluorescence, and immunoprecipitation. Ubiquitin levels of related protein substrates in LM3 and HUH7 cells were compared in negative control, SYVN1 knockdown, and SYVN1 overexpression groups. Results In this study, our whole‐cell proteomic dataset and ubiquitinomic dataset contained approximately 5600 proteins and 12,000 ubiquitinated sites. We discovered increased ubiquitinated sites with shorter ubiquitin chains during the progression of HCC metastasis. In addition, proteomic and ubiquitinomic analyses revealed that high expression of E3 ubiquitin‐protein ligase SYVN1 is related with tumor metastasis. Furthermore, we found that SYVN1 interacted with heat shock protein 90 (HSP90) and impacted the ubiquitination of eukaryotic elongation factor 2 kinase (EEF2K). Conclusions The ubiquitination profiles of HCC with and without vascular invasion were significantly different. SYVN1 was the most important E3 ubiquitin‐protein ligase responsible for this phenomenon, and it was related with tumor metastasis and growth. Therefore, SYVN1 might be a potential therapeutic target for HCC. |
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| id | doaj.art-041edc5e7c924d6aa4a5e631d7e06c66 |
| institution | Directory Open Access Journal |
| issn | 2523-3548 |
| language | English |
| last_indexed | 2024-12-18T01:04:43Z |
| publishDate | 2021-10-01 |
| publisher | Wiley |
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| series | Cancer Communications |
| spelling | doaj.art-041edc5e7c924d6aa4a5e631d7e06c662022-12-21T21:26:16ZengWileyCancer Communications2523-35482021-10-0141101007102310.1002/cac2.12192Integrative proteomics reveals the role of E3 ubiquitin ligase SYVN1 in hepatocellular carcinoma metastasisFeiyang Ji0Menghao Zhou1Zeyu Sun2Zhengyi Jiang3Huihui Zhu4Zhongyang Xie5Xiaoxi Ouyang6Lingjian Zhang7Lanjuan Li8State Key Laboratory for Diagnosis and Treatment of Infectious Diseases The First Affiliated Hospital School of Medicine Zhejiang University Hangzhou Zhejiang 310003 P. R. ChinaState Key Laboratory for Diagnosis and Treatment of Infectious Diseases The First Affiliated Hospital School of Medicine Zhejiang University Hangzhou Zhejiang 310003 P. R. ChinaState Key Laboratory for Diagnosis and Treatment of Infectious Diseases The First Affiliated Hospital School of Medicine Zhejiang University Hangzhou Zhejiang 310003 P. R. ChinaState Key Laboratory for Diagnosis and Treatment of Infectious Diseases The First Affiliated Hospital School of Medicine Zhejiang University Hangzhou Zhejiang 310003 P. R. ChinaDepartment of Hepatobiliary and Pancreatic Surgery The First Affiliated Hospital School of Medicine Zhejiang University Hangzhou Zhejiang 310003 P. R. ChinaState Key Laboratory for Diagnosis and Treatment of Infectious Diseases The First Affiliated Hospital School of Medicine Zhejiang University Hangzhou Zhejiang 310003 P. R. ChinaState Key Laboratory for Diagnosis and Treatment of Infectious Diseases The First Affiliated Hospital School of Medicine Zhejiang University Hangzhou Zhejiang 310003 P. R. ChinaState Key Laboratory for Diagnosis and Treatment of Infectious Diseases The First Affiliated Hospital School of Medicine Zhejiang University Hangzhou Zhejiang 310003 P. R. ChinaState Key Laboratory for Diagnosis and Treatment of Infectious Diseases The First Affiliated Hospital School of Medicine Zhejiang University Hangzhou Zhejiang 310003 P. R. ChinaAbstract Background Tumor metastasis is a major factor for poor prognosis of hepatocellular carcinoma (HCC), but the relationship between ubiquitination and metastasis need to be studied more systematically. We analyzed the ubiquitinome of HCC in this study to have a more comprehensive insight into human HCC metastasis. Methods The protein ubiquitination levels in 15 HCC specimens with vascular invasion and 15 without vascular invasion were detected by ubiquitinome. Proteins with significantly different ubiquitination levels between HCCs with and without vascular invasion were used to predict E3 ubiquitin ligases associated with tumor metastasis. The topological network of protein substrates and corresponding E3 ubiquitin ligases was constructed to identify the key E3 ubiquitin ligase. Besides, the growth, migration and invasion ability of LM3 and HUH7 hepatoma cell lines with and without SYVN1 expression interference were measured by cell proliferation assay, subcutaneous tumor assay, umphal vein endothelium tube formation assay, transwell migration and invasion assays. Finally, the interacting proteins of SYVN1 were screened and verified by protein interaction omics, immunofluorescence, and immunoprecipitation. Ubiquitin levels of related protein substrates in LM3 and HUH7 cells were compared in negative control, SYVN1 knockdown, and SYVN1 overexpression groups. Results In this study, our whole‐cell proteomic dataset and ubiquitinomic dataset contained approximately 5600 proteins and 12,000 ubiquitinated sites. We discovered increased ubiquitinated sites with shorter ubiquitin chains during the progression of HCC metastasis. In addition, proteomic and ubiquitinomic analyses revealed that high expression of E3 ubiquitin‐protein ligase SYVN1 is related with tumor metastasis. Furthermore, we found that SYVN1 interacted with heat shock protein 90 (HSP90) and impacted the ubiquitination of eukaryotic elongation factor 2 kinase (EEF2K). Conclusions The ubiquitination profiles of HCC with and without vascular invasion were significantly different. SYVN1 was the most important E3 ubiquitin‐protein ligase responsible for this phenomenon, and it was related with tumor metastasis and growth. Therefore, SYVN1 might be a potential therapeutic target for HCC.https://doi.org/10.1002/cac2.12192cancerE3 ubiquitin‐protein ligaseeukaryotic elongation factor 2 kinaseheat shock protein 90hepatocellular carcinomaliver |
| spellingShingle | Feiyang Ji Menghao Zhou Zeyu Sun Zhengyi Jiang Huihui Zhu Zhongyang Xie Xiaoxi Ouyang Lingjian Zhang Lanjuan Li Integrative proteomics reveals the role of E3 ubiquitin ligase SYVN1 in hepatocellular carcinoma metastasis Cancer Communications cancer E3 ubiquitin‐protein ligase eukaryotic elongation factor 2 kinase heat shock protein 90 hepatocellular carcinoma liver |
| title | Integrative proteomics reveals the role of E3 ubiquitin ligase SYVN1 in hepatocellular carcinoma metastasis |
| title_full | Integrative proteomics reveals the role of E3 ubiquitin ligase SYVN1 in hepatocellular carcinoma metastasis |
| title_fullStr | Integrative proteomics reveals the role of E3 ubiquitin ligase SYVN1 in hepatocellular carcinoma metastasis |
| title_full_unstemmed | Integrative proteomics reveals the role of E3 ubiquitin ligase SYVN1 in hepatocellular carcinoma metastasis |
| title_short | Integrative proteomics reveals the role of E3 ubiquitin ligase SYVN1 in hepatocellular carcinoma metastasis |
| title_sort | integrative proteomics reveals the role of e3 ubiquitin ligase syvn1 in hepatocellular carcinoma metastasis |
| topic | cancer E3 ubiquitin‐protein ligase eukaryotic elongation factor 2 kinase heat shock protein 90 hepatocellular carcinoma liver |
| url | https://doi.org/10.1002/cac2.12192 |
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