Artemisitene suppresses rheumatoid arthritis progression via modulating METTL3‐mediated N6‐methyladenosine modification of ICAM2 mRNA in fibroblast‐like synoviocytes
Abstract Background Rheumatoid arthritis (RA) is a chronic autoimmune disease. We previously revealed that the natural compound artemisitene (ATT) exhibits excellent broad anticancer activities without toxicity on normal tissues. Nevertheless, the effect of ATT on RA is undiscovered. Herein, we aim...
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Wiley
2022-12-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.1148 |
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| author | Jian Chen Xian Lin Juan He Dandan Liu Lianhua He Miaomiao Zhang Huijie Luan Yiping Hu Cheng Tao Qingwen Wang |
| author_facet | Jian Chen Xian Lin Juan He Dandan Liu Lianhua He Miaomiao Zhang Huijie Luan Yiping Hu Cheng Tao Qingwen Wang |
| author_sort | Jian Chen |
| collection | DOAJ |
| description | Abstract Background Rheumatoid arthritis (RA) is a chronic autoimmune disease. We previously revealed that the natural compound artemisitene (ATT) exhibits excellent broad anticancer activities without toxicity on normal tissues. Nevertheless, the effect of ATT on RA is undiscovered. Herein, we aim to study the effect and potential mechanism of ATT on RA management. Methods A collagen‐induced arthritis (CIA) mouse model was employed to confirm the anti‐RA potential of ATT. Cell Counting Kit‐8 (CCK‐8) and 5‐ethynyl‐2'‐deoxyuridine (EdU) assays, cell cycle and apoptosis analysis, immunofluorescence, migration and invasion assays, quantitative real‐time PCR (RT‐qPCR), Western blot, RNA‐sequencing (RNA‐seq) analysis, plasmid construction and lentivirus infection, and methylated RNA immunoprecipitation and chromatin immunoprecipitation assays, were carried out to confirm the effect and potential mechanism of ATT on RA management. Results ATT relieved CIA in mice. ATT inhibited proliferation and induced apoptosis of RA‐fibroblast‐like synoviocytes (FLSs). ATT restrained RA‐FLSs migration and invasion via suppressing epithelial–mesenchymal transition. RNA‐sequencing analysis and bioinformatics analysis identified intercellular adhesion molecule 2 (ICAM2) as a promoter of RA progression in RA‐FLSs. ATT inhibits RA progression by suppressing ICAM2/phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT)/p300 pathway in RA‐FLSs. Moreover, ATT inhibited methyltransferase‐like 3 (METTL3)‐mediated N6‐methyladenosine methylation of ICAM2 mRNA in RA‐FLSs. Interestingly, p300 directly facilitated METTL3 transcription, which could be restrained by ATT in RA‐FLSs. Importantly, METTL3, ICAM2 and p300 expressions in synovium tissues of RA patients were related to clinical characteristics and therapy response. Conclusions We provided strong evidence that ATT has therapeutic potential for RA management by suppressing proliferation, migration and invasion, in addition to inducing apoptosis of RA‐FLSs through modulating METTL3/ICAM2/PI3K/AKT/p300 feedback loop, supplying the fundamental basis for the clinical application of ATT in RA therapy. Moreover, METTL3, ICAM2 and p300 might serve as biomarkers for the therapy response of RA patients. |
| first_indexed | 2024-04-10T20:34:11Z |
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| id | doaj.art-b8bf8362c25748d8bf67a1c5d42db9b7 |
| institution | Directory Open Access Journal |
| issn | 2001-1326 |
| language | English |
| last_indexed | 2024-04-10T20:34:11Z |
| publishDate | 2022-12-01 |
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| series | Clinical and Translational Medicine |
| spelling | doaj.art-b8bf8362c25748d8bf67a1c5d42db9b72023-01-25T04:06:34ZengWileyClinical and Translational Medicine2001-13262022-12-011212n/an/a10.1002/ctm2.1148Artemisitene suppresses rheumatoid arthritis progression via modulating METTL3‐mediated N6‐methyladenosine modification of ICAM2 mRNA in fibroblast‐like synoviocytesJian Chen0Xian Lin1Juan He2Dandan Liu3Lianhua He4Miaomiao Zhang5Huijie Luan6Yiping Hu7Cheng Tao8Qingwen Wang9Department of Rheumatism and Immunology Peking University Shenzhen Hospital Shenzhen Guangdong ChinaDepartment of Rheumatism and Immunology Peking University Shenzhen Hospital Shenzhen Guangdong ChinaDepartment of Rheumatism and Immunology Peking University Shenzhen Hospital Shenzhen Guangdong ChinaSchool of Basic Medical Science Guangzhou University of Chinese Medicine Guangzhou Guangdong ChinaDepartment of Rheumatism and Immunology Peking University Shenzhen Hospital Shenzhen Guangdong ChinaDepartment of Rheumatism and Immunology Peking University Shenzhen Hospital Shenzhen Guangdong ChinaDepartment of Rheumatism and Immunology Peking University Shenzhen Hospital Shenzhen Guangdong ChinaDepartment of Rheumatism and Immunology Peking University Shenzhen Hospital Shenzhen Guangdong ChinaSchool of Pharmacy Guangdong Medical University Dongguan Guangdong ChinaDepartment of Rheumatism and Immunology Peking University Shenzhen Hospital Shenzhen Guangdong ChinaAbstract Background Rheumatoid arthritis (RA) is a chronic autoimmune disease. We previously revealed that the natural compound artemisitene (ATT) exhibits excellent broad anticancer activities without toxicity on normal tissues. Nevertheless, the effect of ATT on RA is undiscovered. Herein, we aim to study the effect and potential mechanism of ATT on RA management. Methods A collagen‐induced arthritis (CIA) mouse model was employed to confirm the anti‐RA potential of ATT. Cell Counting Kit‐8 (CCK‐8) and 5‐ethynyl‐2'‐deoxyuridine (EdU) assays, cell cycle and apoptosis analysis, immunofluorescence, migration and invasion assays, quantitative real‐time PCR (RT‐qPCR), Western blot, RNA‐sequencing (RNA‐seq) analysis, plasmid construction and lentivirus infection, and methylated RNA immunoprecipitation and chromatin immunoprecipitation assays, were carried out to confirm the effect and potential mechanism of ATT on RA management. Results ATT relieved CIA in mice. ATT inhibited proliferation and induced apoptosis of RA‐fibroblast‐like synoviocytes (FLSs). ATT restrained RA‐FLSs migration and invasion via suppressing epithelial–mesenchymal transition. RNA‐sequencing analysis and bioinformatics analysis identified intercellular adhesion molecule 2 (ICAM2) as a promoter of RA progression in RA‐FLSs. ATT inhibits RA progression by suppressing ICAM2/phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT)/p300 pathway in RA‐FLSs. Moreover, ATT inhibited methyltransferase‐like 3 (METTL3)‐mediated N6‐methyladenosine methylation of ICAM2 mRNA in RA‐FLSs. Interestingly, p300 directly facilitated METTL3 transcription, which could be restrained by ATT in RA‐FLSs. Importantly, METTL3, ICAM2 and p300 expressions in synovium tissues of RA patients were related to clinical characteristics and therapy response. Conclusions We provided strong evidence that ATT has therapeutic potential for RA management by suppressing proliferation, migration and invasion, in addition to inducing apoptosis of RA‐FLSs through modulating METTL3/ICAM2/PI3K/AKT/p300 feedback loop, supplying the fundamental basis for the clinical application of ATT in RA therapy. Moreover, METTL3, ICAM2 and p300 might serve as biomarkers for the therapy response of RA patients.https://doi.org/10.1002/ctm2.1148artemisitenefibroblast‐like synoviocytesICAM2METTL3rheumatoid arthritis |
| spellingShingle | Jian Chen Xian Lin Juan He Dandan Liu Lianhua He Miaomiao Zhang Huijie Luan Yiping Hu Cheng Tao Qingwen Wang Artemisitene suppresses rheumatoid arthritis progression via modulating METTL3‐mediated N6‐methyladenosine modification of ICAM2 mRNA in fibroblast‐like synoviocytes Clinical and Translational Medicine artemisitene fibroblast‐like synoviocytes ICAM2 METTL3 rheumatoid arthritis |
| title | Artemisitene suppresses rheumatoid arthritis progression via modulating METTL3‐mediated N6‐methyladenosine modification of ICAM2 mRNA in fibroblast‐like synoviocytes |
| title_full | Artemisitene suppresses rheumatoid arthritis progression via modulating METTL3‐mediated N6‐methyladenosine modification of ICAM2 mRNA in fibroblast‐like synoviocytes |
| title_fullStr | Artemisitene suppresses rheumatoid arthritis progression via modulating METTL3‐mediated N6‐methyladenosine modification of ICAM2 mRNA in fibroblast‐like synoviocytes |
| title_full_unstemmed | Artemisitene suppresses rheumatoid arthritis progression via modulating METTL3‐mediated N6‐methyladenosine modification of ICAM2 mRNA in fibroblast‐like synoviocytes |
| title_short | Artemisitene suppresses rheumatoid arthritis progression via modulating METTL3‐mediated N6‐methyladenosine modification of ICAM2 mRNA in fibroblast‐like synoviocytes |
| title_sort | artemisitene suppresses rheumatoid arthritis progression via modulating mettl3 mediated n6 methyladenosine modification of icam2 mrna in fibroblast like synoviocytes |
| topic | artemisitene fibroblast‐like synoviocytes ICAM2 METTL3 rheumatoid arthritis |
| url | https://doi.org/10.1002/ctm2.1148 |
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