MKRN1 promotes colorectal cancer metastasis by activating the TGF-β signalling pathway through SNIP1 protein degradation
Abstract Background The Makorin ring finger protein 1 (MKRN1) gene, also called RNF61, is located on the long arm of chromosome 7 and is a member of the RING finger protein family. The E3 ubiquitin ligase MKRN1 is closely linked to tumour development, but the exact mechanism needs to be elucidated....
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-08-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-023-02788-w |
| _version_ | 1797555651982917632 |
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| author | Yi Zhang Qin-shan Li Hong-lin Liu Hong-ting Tang Han-lin Yang Dao-qiu Wu Yu-ying Huang Li-cheng Li Li-hong Liu Meng-xing Li |
| author_facet | Yi Zhang Qin-shan Li Hong-lin Liu Hong-ting Tang Han-lin Yang Dao-qiu Wu Yu-ying Huang Li-cheng Li Li-hong Liu Meng-xing Li |
| author_sort | Yi Zhang |
| collection | DOAJ |
| description | Abstract Background The Makorin ring finger protein 1 (MKRN1) gene, also called RNF61, is located on the long arm of chromosome 7 and is a member of the RING finger protein family. The E3 ubiquitin ligase MKRN1 is closely linked to tumour development, but the exact mechanism needs to be elucidated. In this study, we aimed to investigate the specific mechanism and role of MKRN1 in colorectal cancer (CRC) development. Methods MKRN1 expression in CRC was analysed using the Cancer Cell Line Encyclopaedia and the Cancer Genome Atlas (TCGA) databases. Rectal tumour tissues were frozen to explore the MKRN1 expression in CRC and its clinical significance. The impact of MKRN1 on CRC cell proliferation and migration was observed using CCK8, colony formation, wound healing, and transwell assays. A combination of MKRN1 quantitative proteomics, ubiquitination modification omics analysis, and a string of in vitro and in vivo experiments revealed the potential mechanisms by which MKRN1 regulates CRC metastasis. Results MKRN1 expression was significantly elevated in CRC tissues compared to paracancerous tissues and was positively linked with prognosis (P < 0.01). MKRN1 downregulation inhibits CRC cell proliferation, migration, and invasion. Conversely, MKRN1 overexpression promotes the proliferation, migration, and invasion of CRC cells. Mechanistically, MKRN1 induces epithelial-mesenchymal transition (EMT) in CRC cells via ubiquitination and degradation of Smad nuclear-interacting protein 1 (SNIP1). Furthermore, SNIP1 inhibits transforming growth factor-β (TGF-β) signalling, and MKRN1 promotes TGF-β signalling by degrading SNIP1 to induce EMT in CRC cells. Finally, using conditional knockout mice, intestinal lesions and metastatic liver microlesions were greatly reduced in the intestinal knockout MKRN1 group compared to that in the control group. Conclusions High MKRN1 levels promote TGF-β signalling through ubiquitination and degradation of SNIP1, thereby facilitating CRC metastasis, and supporting MKRN1 as a CRC pro-cancer factor. The MKRN1/SNIP1/TGF-β axis may be a potential therapeutic target in CRC. |
| first_indexed | 2024-03-10T16:50:33Z |
| format | Article |
| id | doaj.art-311ca7fe21844ae4964e5e1eb201ea1c |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-03-10T16:50:33Z |
| publishDate | 2023-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-311ca7fe21844ae4964e5e1eb201ea1c2023-11-20T11:18:25ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662023-08-0142111710.1186/s13046-023-02788-wMKRN1 promotes colorectal cancer metastasis by activating the TGF-β signalling pathway through SNIP1 protein degradationYi Zhang0Qin-shan Li1Hong-lin Liu2Hong-ting Tang3Han-lin Yang4Dao-qiu Wu5Yu-ying Huang6Li-cheng Li7Li-hong Liu8Meng-xing Li9Guizhou Prenatal Diagnosis Center, Affiliated Hospital of Guizhou Medical UniversityGuizhou Prenatal Diagnosis Center, Affiliated Hospital of Guizhou Medical UniversityInstitute of Clinical Medical Sciences, China-Japan Friendship HospitalDepartment of Clinical Biochemistry, School of Medical Laboratory Science, Guizhou Medical UniversityDepartment of Clinical Biochemistry, School of Medical Laboratory Science, Guizhou Medical UniversityDepartment of Clinical Biochemistry, School of Medical Laboratory Science, Guizhou Medical UniversityDepartment of Clinical Biochemistry, School of Medical Laboratory Science, Guizhou Medical UniversityClinical Medical College, Guizhou Medical UniversityDepartment of Pharmacy, China-Japan Friendship HospitalClinical Medical College, Guizhou Medical UniversityAbstract Background The Makorin ring finger protein 1 (MKRN1) gene, also called RNF61, is located on the long arm of chromosome 7 and is a member of the RING finger protein family. The E3 ubiquitin ligase MKRN1 is closely linked to tumour development, but the exact mechanism needs to be elucidated. In this study, we aimed to investigate the specific mechanism and role of MKRN1 in colorectal cancer (CRC) development. Methods MKRN1 expression in CRC was analysed using the Cancer Cell Line Encyclopaedia and the Cancer Genome Atlas (TCGA) databases. Rectal tumour tissues were frozen to explore the MKRN1 expression in CRC and its clinical significance. The impact of MKRN1 on CRC cell proliferation and migration was observed using CCK8, colony formation, wound healing, and transwell assays. A combination of MKRN1 quantitative proteomics, ubiquitination modification omics analysis, and a string of in vitro and in vivo experiments revealed the potential mechanisms by which MKRN1 regulates CRC metastasis. Results MKRN1 expression was significantly elevated in CRC tissues compared to paracancerous tissues and was positively linked with prognosis (P < 0.01). MKRN1 downregulation inhibits CRC cell proliferation, migration, and invasion. Conversely, MKRN1 overexpression promotes the proliferation, migration, and invasion of CRC cells. Mechanistically, MKRN1 induces epithelial-mesenchymal transition (EMT) in CRC cells via ubiquitination and degradation of Smad nuclear-interacting protein 1 (SNIP1). Furthermore, SNIP1 inhibits transforming growth factor-β (TGF-β) signalling, and MKRN1 promotes TGF-β signalling by degrading SNIP1 to induce EMT in CRC cells. Finally, using conditional knockout mice, intestinal lesions and metastatic liver microlesions were greatly reduced in the intestinal knockout MKRN1 group compared to that in the control group. Conclusions High MKRN1 levels promote TGF-β signalling through ubiquitination and degradation of SNIP1, thereby facilitating CRC metastasis, and supporting MKRN1 as a CRC pro-cancer factor. The MKRN1/SNIP1/TGF-β axis may be a potential therapeutic target in CRC.https://doi.org/10.1186/s13046-023-02788-wColorectal cancerMKRN1MetastasisSNIP1TGF-β signalling |
| spellingShingle | Yi Zhang Qin-shan Li Hong-lin Liu Hong-ting Tang Han-lin Yang Dao-qiu Wu Yu-ying Huang Li-cheng Li Li-hong Liu Meng-xing Li MKRN1 promotes colorectal cancer metastasis by activating the TGF-β signalling pathway through SNIP1 protein degradation Journal of Experimental & Clinical Cancer Research Colorectal cancer MKRN1 Metastasis SNIP1 TGF-β signalling |
| title | MKRN1 promotes colorectal cancer metastasis by activating the TGF-β signalling pathway through SNIP1 protein degradation |
| title_full | MKRN1 promotes colorectal cancer metastasis by activating the TGF-β signalling pathway through SNIP1 protein degradation |
| title_fullStr | MKRN1 promotes colorectal cancer metastasis by activating the TGF-β signalling pathway through SNIP1 protein degradation |
| title_full_unstemmed | MKRN1 promotes colorectal cancer metastasis by activating the TGF-β signalling pathway through SNIP1 protein degradation |
| title_short | MKRN1 promotes colorectal cancer metastasis by activating the TGF-β signalling pathway through SNIP1 protein degradation |
| title_sort | mkrn1 promotes colorectal cancer metastasis by activating the tgf β signalling pathway through snip1 protein degradation |
| topic | Colorectal cancer MKRN1 Metastasis SNIP1 TGF-β signalling |
| url | https://doi.org/10.1186/s13046-023-02788-w |
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