Flavokawain A is a natural inhibitor of PRMT5 in bladder cancer
Abstract Background Protein arginine methyltransferases (PRMTs) regulate protein biological activity by modulating arginine methylation in cancer and are increasingly recognized as potential drug targets. Inhibitors targeting PRMTs are currently in the early phases of clinical trials and more candid...
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| Format: | Article |
| Language: | English |
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BMC
2022-10-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-022-02500-4 |
| _version_ | 1817979743734071296 |
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| author | Shuangjie Liu Zhuonan Liu Chiyuan Piao Zhe Zhang Chuize Kong Lei Yin Xi Liu |
| author_facet | Shuangjie Liu Zhuonan Liu Chiyuan Piao Zhe Zhang Chuize Kong Lei Yin Xi Liu |
| author_sort | Shuangjie Liu |
| collection | DOAJ |
| description | Abstract Background Protein arginine methyltransferases (PRMTs) regulate protein biological activity by modulating arginine methylation in cancer and are increasingly recognized as potential drug targets. Inhibitors targeting PRMTs are currently in the early phases of clinical trials and more candidate drugs are needed. Flavokawain A (FKA), extracted from kava plant, has been recognized as a potential chemotherapy drug in bladder cancer (BC), but its action mechanism remains unclear. Methods We first determined the role of a type II PRMT, PRMT5, in BC tissue samples and performed cytological experiments. We then utilized bioinformatics tools, including computational simulation, virtual screening, molecular docking, and energy analysis, to identify the potential use of PRMT5 inhibitors for BC treatment. In vitro and in vivo co-IP and mutation assays were performed to elucidate the molecular mechanism of PRMT5 inhibitor. Pharmacology experiments like bio-layer interferometry, CETSA, and pull-down assays were further used to provide direct evidence of the complex binding process. Results Among PRMTs, PRMT5 was identified as a therapeutic target for BC. PRMT5 expression in BC was correlated with poor prognosis and manipulating its expression could affect cancer cell growth. Through screening and extensive experimental validation, we recognized that a natural product, FKA, was a small new inhibitor molecule for PRMT5. We noticed that the product could inhibit the action of BC, in vitro and in vivo, by inhibiting PRMT5. We further demonstrated that FKA blocks the symmetric arginine dimethylation of histone H2A and H4 by binding to Y304 and F580 of PRMT5. Conclusions In summary, our research strongly suggests that PRMT5 is a potential epigenetic therapeutic target in bladder cancer, and that FKA can be used as a targeted inhibitor of PRMT5 for the treatment of bladder cancer. |
| first_indexed | 2024-04-13T22:45:31Z |
| format | Article |
| id | doaj.art-649aac8a497d456186ed234f7d1bce6c |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-04-13T22:45:31Z |
| publishDate | 2022-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-649aac8a497d456186ed234f7d1bce6c2022-12-22T02:26:24ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662022-10-0141111510.1186/s13046-022-02500-4Flavokawain A is a natural inhibitor of PRMT5 in bladder cancerShuangjie Liu0Zhuonan Liu1Chiyuan Piao2Zhe Zhang3Chuize Kong4Lei Yin5Xi Liu6Department of Urology, The First Hospital of China Medical UniversityDepartment of Urology, The First Hospital of China Medical UniversityDepartment of Urology, The First Hospital of China Medical UniversityDepartment of Urology, The First Hospital of China Medical UniversityDepartment of Urology, The First Hospital of China Medical UniversityDepartment of Urology, The First Hospital of China Medical UniversityDepartment of Urology, The First Hospital of China Medical UniversityAbstract Background Protein arginine methyltransferases (PRMTs) regulate protein biological activity by modulating arginine methylation in cancer and are increasingly recognized as potential drug targets. Inhibitors targeting PRMTs are currently in the early phases of clinical trials and more candidate drugs are needed. Flavokawain A (FKA), extracted from kava plant, has been recognized as a potential chemotherapy drug in bladder cancer (BC), but its action mechanism remains unclear. Methods We first determined the role of a type II PRMT, PRMT5, in BC tissue samples and performed cytological experiments. We then utilized bioinformatics tools, including computational simulation, virtual screening, molecular docking, and energy analysis, to identify the potential use of PRMT5 inhibitors for BC treatment. In vitro and in vivo co-IP and mutation assays were performed to elucidate the molecular mechanism of PRMT5 inhibitor. Pharmacology experiments like bio-layer interferometry, CETSA, and pull-down assays were further used to provide direct evidence of the complex binding process. Results Among PRMTs, PRMT5 was identified as a therapeutic target for BC. PRMT5 expression in BC was correlated with poor prognosis and manipulating its expression could affect cancer cell growth. Through screening and extensive experimental validation, we recognized that a natural product, FKA, was a small new inhibitor molecule for PRMT5. We noticed that the product could inhibit the action of BC, in vitro and in vivo, by inhibiting PRMT5. We further demonstrated that FKA blocks the symmetric arginine dimethylation of histone H2A and H4 by binding to Y304 and F580 of PRMT5. Conclusions In summary, our research strongly suggests that PRMT5 is a potential epigenetic therapeutic target in bladder cancer, and that FKA can be used as a targeted inhibitor of PRMT5 for the treatment of bladder cancer.https://doi.org/10.1186/s13046-022-02500-4Protein arginine methyltransferaseFlavokawain ABladder cancerMethylation disorderArginine methylation |
| spellingShingle | Shuangjie Liu Zhuonan Liu Chiyuan Piao Zhe Zhang Chuize Kong Lei Yin Xi Liu Flavokawain A is a natural inhibitor of PRMT5 in bladder cancer Journal of Experimental & Clinical Cancer Research Protein arginine methyltransferase Flavokawain A Bladder cancer Methylation disorder Arginine methylation |
| title | Flavokawain A is a natural inhibitor of PRMT5 in bladder cancer |
| title_full | Flavokawain A is a natural inhibitor of PRMT5 in bladder cancer |
| title_fullStr | Flavokawain A is a natural inhibitor of PRMT5 in bladder cancer |
| title_full_unstemmed | Flavokawain A is a natural inhibitor of PRMT5 in bladder cancer |
| title_short | Flavokawain A is a natural inhibitor of PRMT5 in bladder cancer |
| title_sort | flavokawain a is a natural inhibitor of prmt5 in bladder cancer |
| topic | Protein arginine methyltransferase Flavokawain A Bladder cancer Methylation disorder Arginine methylation |
| url | https://doi.org/10.1186/s13046-022-02500-4 |
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