A tumor suppressor protein encoded by circKEAP1 inhibits osteosarcoma cell stemness and metastasis by promoting vimentin proteasome degradation and activating anti-tumor immunity
Abstract Background Osteosarcoma (OS) is one of most commonly diagnosed bone cancer. Circular RNAs (circRNAs) are a class of highly stable non-coding RNA, the majority of which have not been characterized functionally. The underlying function and molecular mechanisms of circRNAs in OS have not been...
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| Format: | Article |
| Language: | English |
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BMC
2024-02-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-024-02971-7 |
| _version_ | 1797272783779004416 |
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| author | Ying Zhang Zhaoyong Liu Zhigang Zhong Yanchen Ji Huancheng Guo Weidong Wang Chuangzhen Chen |
| author_facet | Ying Zhang Zhaoyong Liu Zhigang Zhong Yanchen Ji Huancheng Guo Weidong Wang Chuangzhen Chen |
| author_sort | Ying Zhang |
| collection | DOAJ |
| description | Abstract Background Osteosarcoma (OS) is one of most commonly diagnosed bone cancer. Circular RNAs (circRNAs) are a class of highly stable non-coding RNA, the majority of which have not been characterized functionally. The underlying function and molecular mechanisms of circRNAs in OS have not been fully demonstrated. Method Microarray analysis was performed to identify circRNAs that are differentially-expressed between OS and corresponding normal tissues. The biological function of circKEAP1 was confirmed in vitro and in vivo. Mass spectrometry and western blot assays were used to identify the circKEAP1-encoded protein KEAP1-259aa. The molecular mechanism of circKEAP1 was investigated by RNA sequencing and RNA immunoprecipitation analyses. Results Here, we identified a tumor suppressor circKEAP1, originating from the back-splicing of exon2 of the KEAP1 gene. Clinically, circKEAP1 is downregulated in OS tumors and associated with better survival in cancer patients. N6-methyladenosine (m6A) at a specific adenosine leads to low expression of circKEAP1. Further analysis revealed that circKEAP1 contained a 777 nt long ORF and encoded a truncated protein KEAP1-259aa that reduces cell proliferation, invasion and tumorsphere formation of OS cells. Mechanistically, KEAP1-259aa bound to vimentin in the cytoplasm to promote vimentin proteasome degradation by interacting with the E3 ligase ARIH1. Moreover, circKEAP1 interacted with RIG-I to activate anti-tumor immunity via the IFN-γ pathway. Conclusion Taken together, our findings characterize a tumor suppressor circKEAP1 as a key tumor suppressor regulating of OS cell stemness, proliferation and migration, providing potential therapeutic targets for treatment of OS. |
| first_indexed | 2024-03-07T14:34:48Z |
| format | Article |
| id | doaj.art-c218ad3f38f049ecbc391db0ff32ac03 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-03-07T14:34:48Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-c218ad3f38f049ecbc391db0ff32ac032024-03-05T20:43:25ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662024-02-0143112010.1186/s13046-024-02971-7A tumor suppressor protein encoded by circKEAP1 inhibits osteosarcoma cell stemness and metastasis by promoting vimentin proteasome degradation and activating anti-tumor immunityYing Zhang0Zhaoyong Liu1Zhigang Zhong2Yanchen Ji3Huancheng Guo4Weidong Wang5Chuangzhen Chen6Department of Radiotherapy, Cancer Hospital of Shantou University Medical CollegeDepartment of Orthopaedics, First Affiliated Hospital of Shantou University Medical CollegeSports Medicine Center, First Affiliated Hospital of Shantou University Medical CollegeDepartment of Radiotherapy, Cancer Hospital of Shantou University Medical CollegeDepartment of Orthopaedics, First Affiliated Hospital of Shantou University Medical CollegeDepartment of Orthopaedics, Cancer Hospital of Shantou University Medical CollegeDepartment of Radiotherapy, Cancer Hospital of Shantou University Medical CollegeAbstract Background Osteosarcoma (OS) is one of most commonly diagnosed bone cancer. Circular RNAs (circRNAs) are a class of highly stable non-coding RNA, the majority of which have not been characterized functionally. The underlying function and molecular mechanisms of circRNAs in OS have not been fully demonstrated. Method Microarray analysis was performed to identify circRNAs that are differentially-expressed between OS and corresponding normal tissues. The biological function of circKEAP1 was confirmed in vitro and in vivo. Mass spectrometry and western blot assays were used to identify the circKEAP1-encoded protein KEAP1-259aa. The molecular mechanism of circKEAP1 was investigated by RNA sequencing and RNA immunoprecipitation analyses. Results Here, we identified a tumor suppressor circKEAP1, originating from the back-splicing of exon2 of the KEAP1 gene. Clinically, circKEAP1 is downregulated in OS tumors and associated with better survival in cancer patients. N6-methyladenosine (m6A) at a specific adenosine leads to low expression of circKEAP1. Further analysis revealed that circKEAP1 contained a 777 nt long ORF and encoded a truncated protein KEAP1-259aa that reduces cell proliferation, invasion and tumorsphere formation of OS cells. Mechanistically, KEAP1-259aa bound to vimentin in the cytoplasm to promote vimentin proteasome degradation by interacting with the E3 ligase ARIH1. Moreover, circKEAP1 interacted with RIG-I to activate anti-tumor immunity via the IFN-γ pathway. Conclusion Taken together, our findings characterize a tumor suppressor circKEAP1 as a key tumor suppressor regulating of OS cell stemness, proliferation and migration, providing potential therapeutic targets for treatment of OS.https://doi.org/10.1186/s13046-024-02971-7circKEAP1OsteosarcomaVimentinARIH1 |
| spellingShingle | Ying Zhang Zhaoyong Liu Zhigang Zhong Yanchen Ji Huancheng Guo Weidong Wang Chuangzhen Chen A tumor suppressor protein encoded by circKEAP1 inhibits osteosarcoma cell stemness and metastasis by promoting vimentin proteasome degradation and activating anti-tumor immunity Journal of Experimental & Clinical Cancer Research circKEAP1 Osteosarcoma Vimentin ARIH1 |
| title | A tumor suppressor protein encoded by circKEAP1 inhibits osteosarcoma cell stemness and metastasis by promoting vimentin proteasome degradation and activating anti-tumor immunity |
| title_full | A tumor suppressor protein encoded by circKEAP1 inhibits osteosarcoma cell stemness and metastasis by promoting vimentin proteasome degradation and activating anti-tumor immunity |
| title_fullStr | A tumor suppressor protein encoded by circKEAP1 inhibits osteosarcoma cell stemness and metastasis by promoting vimentin proteasome degradation and activating anti-tumor immunity |
| title_full_unstemmed | A tumor suppressor protein encoded by circKEAP1 inhibits osteosarcoma cell stemness and metastasis by promoting vimentin proteasome degradation and activating anti-tumor immunity |
| title_short | A tumor suppressor protein encoded by circKEAP1 inhibits osteosarcoma cell stemness and metastasis by promoting vimentin proteasome degradation and activating anti-tumor immunity |
| title_sort | tumor suppressor protein encoded by circkeap1 inhibits osteosarcoma cell stemness and metastasis by promoting vimentin proteasome degradation and activating anti tumor immunity |
| topic | circKEAP1 Osteosarcoma Vimentin ARIH1 |
| url | https://doi.org/10.1186/s13046-024-02971-7 |
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