Ube2v1-mediated ubiquitination and degradation of Sirt1 promotes metastasis of colorectal cancer by epigenetically suppressing autophagy
Abstract Background Ubiquitination is a basic post-translational modification for cellular homeostasis, and members of the conjugating enzyme (E2) family are the key components of the ubiquitin–proteasome system. However, the role of E2 family in colorectal cancer (CRC) is largely unknown. Our study...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2018-07-01
|
| Series: | Journal of Hematology & Oncology |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13045-018-0638-9 |
| _version_ | 1818478408714158080 |
|---|---|
| author | Tong Shen Ling-Dong Cai Yu-Hong Liu Shi Li Wen-Juan Gan Xiu-Ming Li Jing-Ru Wang Peng-Da Guo Qun Zhou Xing-Xing Lu Li-Na Sun Jian-Ming Li |
| author_facet | Tong Shen Ling-Dong Cai Yu-Hong Liu Shi Li Wen-Juan Gan Xiu-Ming Li Jing-Ru Wang Peng-Da Guo Qun Zhou Xing-Xing Lu Li-Na Sun Jian-Ming Li |
| author_sort | Tong Shen |
| collection | DOAJ |
| description | Abstract Background Ubiquitination is a basic post-translational modification for cellular homeostasis, and members of the conjugating enzyme (E2) family are the key components of the ubiquitin–proteasome system. However, the role of E2 family in colorectal cancer (CRC) is largely unknown. Our study aimed to investigate the role of Ube2v1, one of the ubiquitin-conjugating E2 enzyme variant proteins (Ube2v) but without the conserved cysteine residue required for the catalytic activity of E2s, in CRC. Methods Immunohistochemistry and real-time RT-PCR were used to study the expressions of Ube2v1 at protein and mRNA levels in CRC, respectively. Western blotting and immunofluorescence, transmission electron microscopy, and in vivo rescue experiments were used to study the functional effects of Ube2v1 on autophagy and EMT program. Quantitative mass spectrometry, immunoprecipitation, ubiquitination assay, western blotting, and real-time RT-PCR were used to analyze the effects of Ube2v1 on histone H4 lysine 16 acetylation, interaction with Sirt1, ubiquitination of Sirt1, and autophagy-related gene expression. Results Ube2v1 was elevated in CRC samples, and its increased expression was correlated with poorer survival of CRC patients. Ube2v1 promoted migration and invasion of CRC cells in vitro and tumor growth and metastasis of CRC cells in vivo. Interestingly, Ube2v1suppressed autophagy program and promoted epithelial mesenchymal transition (EMT) and metastasis of CRC cells in an autophagy-dependent pattern in vitro and in vivo. Moreover, both rapamycin and trehalose attenuated the enhanced Ube2v1-mediated lung metastasis by inducing the autophagy pathway in an orthotropic mouse xenograft model of lung metastasis. Mechanistically, Ube2v1 promoted Ubc13-mediated ubiquitination and degradation of Sirt1 and inhibited histone H4 lysine 16 acetylation, and finally epigenetically suppressed autophagy gene expression in CRC. Conclusions Our study functionally links Ube2v1, an E2 member in the ubiquitin–proteasome system, to autophagy program, thereby shedding light on developing Ube2v1 targeted therapy for CRC patients. |
| first_indexed | 2024-12-10T09:47:44Z |
| format | Article |
| id | doaj.art-51478e4fdac64d20a17045b02eaa93aa |
| institution | Directory Open Access Journal |
| issn | 1756-8722 |
| language | English |
| last_indexed | 2024-12-10T09:47:44Z |
| publishDate | 2018-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Hematology & Oncology |
| spelling | doaj.art-51478e4fdac64d20a17045b02eaa93aa2022-12-22T01:53:45ZengBMCJournal of Hematology & Oncology1756-87222018-07-0111111610.1186/s13045-018-0638-9Ube2v1-mediated ubiquitination and degradation of Sirt1 promotes metastasis of colorectal cancer by epigenetically suppressing autophagyTong Shen0Ling-Dong Cai1Yu-Hong Liu2Shi Li3Wen-Juan Gan4Xiu-Ming Li5Jing-Ru Wang6Peng-Da Guo7Qun Zhou8Xing-Xing Lu9Li-Na Sun10Jian-Ming Li11Department of Pathology, Soochow University Medical SchoolDepartment of Pathology, Soochow University Medical SchoolDepartment of Pathology, Baoan Hospital, Southern Medical UniversityDepartment of Pathology, Soochow University Medical SchoolDepartment of Pathology, Soochow University Medical SchoolDepartment of Pathology, Soochow University Medical SchoolDepartment of Pathology, Soochow University Medical SchoolDepartment of Pathology, Soochow University Medical SchoolDepartment of Pathology, Soochow University Medical SchoolDepartment of Pathology, Soochow University Medical SchoolDepartment of Pathology, Soochow University Medical SchoolDepartment of Pathology, Soochow University Medical SchoolAbstract Background Ubiquitination is a basic post-translational modification for cellular homeostasis, and members of the conjugating enzyme (E2) family are the key components of the ubiquitin–proteasome system. However, the role of E2 family in colorectal cancer (CRC) is largely unknown. Our study aimed to investigate the role of Ube2v1, one of the ubiquitin-conjugating E2 enzyme variant proteins (Ube2v) but without the conserved cysteine residue required for the catalytic activity of E2s, in CRC. Methods Immunohistochemistry and real-time RT-PCR were used to study the expressions of Ube2v1 at protein and mRNA levels in CRC, respectively. Western blotting and immunofluorescence, transmission electron microscopy, and in vivo rescue experiments were used to study the functional effects of Ube2v1 on autophagy and EMT program. Quantitative mass spectrometry, immunoprecipitation, ubiquitination assay, western blotting, and real-time RT-PCR were used to analyze the effects of Ube2v1 on histone H4 lysine 16 acetylation, interaction with Sirt1, ubiquitination of Sirt1, and autophagy-related gene expression. Results Ube2v1 was elevated in CRC samples, and its increased expression was correlated with poorer survival of CRC patients. Ube2v1 promoted migration and invasion of CRC cells in vitro and tumor growth and metastasis of CRC cells in vivo. Interestingly, Ube2v1suppressed autophagy program and promoted epithelial mesenchymal transition (EMT) and metastasis of CRC cells in an autophagy-dependent pattern in vitro and in vivo. Moreover, both rapamycin and trehalose attenuated the enhanced Ube2v1-mediated lung metastasis by inducing the autophagy pathway in an orthotropic mouse xenograft model of lung metastasis. Mechanistically, Ube2v1 promoted Ubc13-mediated ubiquitination and degradation of Sirt1 and inhibited histone H4 lysine 16 acetylation, and finally epigenetically suppressed autophagy gene expression in CRC. Conclusions Our study functionally links Ube2v1, an E2 member in the ubiquitin–proteasome system, to autophagy program, thereby shedding light on developing Ube2v1 targeted therapy for CRC patients.http://link.springer.com/article/10.1186/s13045-018-0638-9Ubiquitin-conjugating E2 enzymeAutophagyEpithelial mesenchymal transitionMetastasisColorectal cancer |
| spellingShingle | Tong Shen Ling-Dong Cai Yu-Hong Liu Shi Li Wen-Juan Gan Xiu-Ming Li Jing-Ru Wang Peng-Da Guo Qun Zhou Xing-Xing Lu Li-Na Sun Jian-Ming Li Ube2v1-mediated ubiquitination and degradation of Sirt1 promotes metastasis of colorectal cancer by epigenetically suppressing autophagy Journal of Hematology & Oncology Ubiquitin-conjugating E2 enzyme Autophagy Epithelial mesenchymal transition Metastasis Colorectal cancer |
| title | Ube2v1-mediated ubiquitination and degradation of Sirt1 promotes metastasis of colorectal cancer by epigenetically suppressing autophagy |
| title_full | Ube2v1-mediated ubiquitination and degradation of Sirt1 promotes metastasis of colorectal cancer by epigenetically suppressing autophagy |
| title_fullStr | Ube2v1-mediated ubiquitination and degradation of Sirt1 promotes metastasis of colorectal cancer by epigenetically suppressing autophagy |
| title_full_unstemmed | Ube2v1-mediated ubiquitination and degradation of Sirt1 promotes metastasis of colorectal cancer by epigenetically suppressing autophagy |
| title_short | Ube2v1-mediated ubiquitination and degradation of Sirt1 promotes metastasis of colorectal cancer by epigenetically suppressing autophagy |
| title_sort | ube2v1 mediated ubiquitination and degradation of sirt1 promotes metastasis of colorectal cancer by epigenetically suppressing autophagy |
| topic | Ubiquitin-conjugating E2 enzyme Autophagy Epithelial mesenchymal transition Metastasis Colorectal cancer |
| url | http://link.springer.com/article/10.1186/s13045-018-0638-9 |
| work_keys_str_mv | AT tongshen ube2v1mediatedubiquitinationanddegradationofsirt1promotesmetastasisofcolorectalcancerbyepigeneticallysuppressingautophagy AT lingdongcai ube2v1mediatedubiquitinationanddegradationofsirt1promotesmetastasisofcolorectalcancerbyepigeneticallysuppressingautophagy AT yuhongliu ube2v1mediatedubiquitinationanddegradationofsirt1promotesmetastasisofcolorectalcancerbyepigeneticallysuppressingautophagy AT shili ube2v1mediatedubiquitinationanddegradationofsirt1promotesmetastasisofcolorectalcancerbyepigeneticallysuppressingautophagy AT wenjuangan ube2v1mediatedubiquitinationanddegradationofsirt1promotesmetastasisofcolorectalcancerbyepigeneticallysuppressingautophagy AT xiumingli ube2v1mediatedubiquitinationanddegradationofsirt1promotesmetastasisofcolorectalcancerbyepigeneticallysuppressingautophagy AT jingruwang ube2v1mediatedubiquitinationanddegradationofsirt1promotesmetastasisofcolorectalcancerbyepigeneticallysuppressingautophagy AT pengdaguo ube2v1mediatedubiquitinationanddegradationofsirt1promotesmetastasisofcolorectalcancerbyepigeneticallysuppressingautophagy AT qunzhou ube2v1mediatedubiquitinationanddegradationofsirt1promotesmetastasisofcolorectalcancerbyepigeneticallysuppressingautophagy AT xingxinglu ube2v1mediatedubiquitinationanddegradationofsirt1promotesmetastasisofcolorectalcancerbyepigeneticallysuppressingautophagy AT linasun ube2v1mediatedubiquitinationanddegradationofsirt1promotesmetastasisofcolorectalcancerbyepigeneticallysuppressingautophagy AT jianmingli ube2v1mediatedubiquitinationanddegradationofsirt1promotesmetastasisofcolorectalcancerbyepigeneticallysuppressingautophagy |