EIF4A3-induced Circ_0001187 facilitates AML suppression through promoting ubiquitin-proteasomal degradation of METTL3 and decreasing m6A modification level mediated by miR-499a-5p/RNF113A pathway
Abstract Aberrant expression of circRNAs has been proven to play a crucial role in the progression of acute myeloid leukemia (AML); however, its regulatory mechanism remains unclear. Herein, we identified a novel circRNA, Circ_0001187, which is downregulated in AML patients, and its low level contri...
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| Format: | Article |
| Language: | English |
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BMC
2023-06-01
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| Series: | Biomarker Research |
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| Online Access: | https://doi.org/10.1186/s40364-023-00495-4 |
| _version_ | 1797806610566873088 |
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| author | Xinyu Yang Fengjiao Han Xiang Hu Guosheng Li Hanyang Wu Can Can Yihong Wei Jinting Liu Ruiqing Wang Wenbo Jia Chunyan ji Daoxin Ma |
| author_facet | Xinyu Yang Fengjiao Han Xiang Hu Guosheng Li Hanyang Wu Can Can Yihong Wei Jinting Liu Ruiqing Wang Wenbo Jia Chunyan ji Daoxin Ma |
| author_sort | Xinyu Yang |
| collection | DOAJ |
| description | Abstract Aberrant expression of circRNAs has been proven to play a crucial role in the progression of acute myeloid leukemia (AML); however, its regulatory mechanism remains unclear. Herein, we identified a novel circRNA, Circ_0001187, which is downregulated in AML patients, and its low level contributes to a poor prognosis. We further validated their expression in large-scale samples and found that only the expression of Circ_0001187 was significantly decreased in newly diagnosed (ND) AML patients and increased in patients with hematological complete remission (HCR) compared with controls. Knockdown of Circ_0001187 significantly promoted proliferation and inhibited apoptosis of AML cells in vitro and in vivo, whereas overexpression of Circ _0001187 exerted the opposite effects. Interestingly, we found that Circ_0001187 decreases mRNA m6A modification in AML cells by enhancing METTL3 protein degradation. Mechanistically, Circ_0001187 sponges miR-499a-5p to enhance the expression of E3 ubiquitin ligase RNF113A, which mediates METTL3 ubiquitin/proteasome-dependent degradation via K48-linked polyubiquitin chains. Moreover, we found that the low expression of Circ _0001187 is regulated by promoter DNA methylation and histone acetylation. Collectively, our findings highlight the potential clinical implications of Circ _0001187 as a key tumor suppressor in AML via the miR-499a-5p/RNF113A/METTL3 pathway. |
| first_indexed | 2024-03-13T06:09:53Z |
| format | Article |
| id | doaj.art-e2a732943cf745c382feb7bd6ea57160 |
| institution | Directory Open Access Journal |
| issn | 2050-7771 |
| language | English |
| last_indexed | 2024-03-13T06:09:53Z |
| publishDate | 2023-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Biomarker Research |
| spelling | doaj.art-e2a732943cf745c382feb7bd6ea571602023-06-11T11:21:04ZengBMCBiomarker Research2050-77712023-06-0111112010.1186/s40364-023-00495-4EIF4A3-induced Circ_0001187 facilitates AML suppression through promoting ubiquitin-proteasomal degradation of METTL3 and decreasing m6A modification level mediated by miR-499a-5p/RNF113A pathwayXinyu Yang0Fengjiao Han1Xiang Hu2Guosheng Li3Hanyang Wu4Can Can5Yihong Wei6Jinting Liu7Ruiqing Wang8Wenbo Jia9Chunyan ji10Daoxin Ma11Department of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong UniversityAbstract Aberrant expression of circRNAs has been proven to play a crucial role in the progression of acute myeloid leukemia (AML); however, its regulatory mechanism remains unclear. Herein, we identified a novel circRNA, Circ_0001187, which is downregulated in AML patients, and its low level contributes to a poor prognosis. We further validated their expression in large-scale samples and found that only the expression of Circ_0001187 was significantly decreased in newly diagnosed (ND) AML patients and increased in patients with hematological complete remission (HCR) compared with controls. Knockdown of Circ_0001187 significantly promoted proliferation and inhibited apoptosis of AML cells in vitro and in vivo, whereas overexpression of Circ _0001187 exerted the opposite effects. Interestingly, we found that Circ_0001187 decreases mRNA m6A modification in AML cells by enhancing METTL3 protein degradation. Mechanistically, Circ_0001187 sponges miR-499a-5p to enhance the expression of E3 ubiquitin ligase RNF113A, which mediates METTL3 ubiquitin/proteasome-dependent degradation via K48-linked polyubiquitin chains. Moreover, we found that the low expression of Circ _0001187 is regulated by promoter DNA methylation and histone acetylation. Collectively, our findings highlight the potential clinical implications of Circ _0001187 as a key tumor suppressor in AML via the miR-499a-5p/RNF113A/METTL3 pathway.https://doi.org/10.1186/s40364-023-00495-4Circ_0001187METTL3RNF113AmiR-499a-5pAcute myeloid leukemiaProgression |
| spellingShingle | Xinyu Yang Fengjiao Han Xiang Hu Guosheng Li Hanyang Wu Can Can Yihong Wei Jinting Liu Ruiqing Wang Wenbo Jia Chunyan ji Daoxin Ma EIF4A3-induced Circ_0001187 facilitates AML suppression through promoting ubiquitin-proteasomal degradation of METTL3 and decreasing m6A modification level mediated by miR-499a-5p/RNF113A pathway Biomarker Research Circ_0001187 METTL3 RNF113A miR-499a-5p Acute myeloid leukemia Progression |
| title | EIF4A3-induced Circ_0001187 facilitates AML suppression through promoting ubiquitin-proteasomal degradation of METTL3 and decreasing m6A modification level mediated by miR-499a-5p/RNF113A pathway |
| title_full | EIF4A3-induced Circ_0001187 facilitates AML suppression through promoting ubiquitin-proteasomal degradation of METTL3 and decreasing m6A modification level mediated by miR-499a-5p/RNF113A pathway |
| title_fullStr | EIF4A3-induced Circ_0001187 facilitates AML suppression through promoting ubiquitin-proteasomal degradation of METTL3 and decreasing m6A modification level mediated by miR-499a-5p/RNF113A pathway |
| title_full_unstemmed | EIF4A3-induced Circ_0001187 facilitates AML suppression through promoting ubiquitin-proteasomal degradation of METTL3 and decreasing m6A modification level mediated by miR-499a-5p/RNF113A pathway |
| title_short | EIF4A3-induced Circ_0001187 facilitates AML suppression through promoting ubiquitin-proteasomal degradation of METTL3 and decreasing m6A modification level mediated by miR-499a-5p/RNF113A pathway |
| title_sort | eif4a3 induced circ 0001187 facilitates aml suppression through promoting ubiquitin proteasomal degradation of mettl3 and decreasing m6a modification level mediated by mir 499a 5p rnf113a pathway |
| topic | Circ_0001187 METTL3 RNF113A miR-499a-5p Acute myeloid leukemia Progression |
| url | https://doi.org/10.1186/s40364-023-00495-4 |
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