O-GlcNAcylation of METTL3 drives hepatocellular carcinoma progression by upregulating MCM10 expression in an m6A-IGF2BP3-dependent manner
Abstract The m6A methyltransferase METTL3 is a key regulator of RNA m6A modification, which plays a critical role in cancer development. Despite the significance of METTL3 in hepatocellular carcinoma (HCC), its post-translational modifications and their functional implications in HCC remain poorly u...
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| Format: | Article |
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Nature Publishing Group
2025-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07844-1 |
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| author | Zhen Chen Jiaxin Yin Zhongqi Feng Yanlai Zhang Li Liang Xiaojun Wang Kai Wang Ni Tang |
| author_facet | Zhen Chen Jiaxin Yin Zhongqi Feng Yanlai Zhang Li Liang Xiaojun Wang Kai Wang Ni Tang |
| author_sort | Zhen Chen |
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| description | Abstract The m6A methyltransferase METTL3 is a key regulator of RNA m6A modification, which plays a critical role in cancer development. Despite the significance of METTL3 in hepatocellular carcinoma (HCC), its post-translational modifications and their functional implications in HCC remain poorly understood. The present study reveals that METTL3 undergoes O-GlcNAcylation, which enhances its stability and promotes HCC progression. Specific O-GlcNAcylation sites (T186/S192/S193) in METTL3 are identified. O-GlcNAc modification reduces METTL3 ubiquitination, thereby increasing protein stability, and enhances its interaction with WTAP, thereby sustaining m6A levels in hepatoma cells. Notably, METTL3 O-GlcNAcylation upregulates the expression of minichromosome maintenance protein 10 (MCM10) by stabilizing its mRNA via an m6A-IGF2BP3-dependent manner. Targeting METTL3 O-GlcNAcylation with designed peptides effectively inhibits HCC growth both in vitro and in vivo. Collectively, our findings provide insights into the regulatory role of O-GlcNAcylation in modulating the m6A epitranscriptome and suggest the potential therapeutic relevance of targeting METTL3 O-GlcNAcylation in HCC. |
| format | Article |
| id | doaj-art-0a49c8e2e11b4842b2f907a2b5a7892b |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
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| series | Cell Death and Disease |
| spelling | doaj-art-0a49c8e2e11b4842b2f907a2b5a7892b2025-08-20T03:42:10ZengNature Publishing GroupCell Death and Disease2041-48892025-07-0116111410.1038/s41419-025-07844-1O-GlcNAcylation of METTL3 drives hepatocellular carcinoma progression by upregulating MCM10 expression in an m6A-IGF2BP3-dependent mannerZhen Chen0Jiaxin Yin1Zhongqi Feng2Yanlai Zhang3Li Liang4Xiaojun Wang5Kai Wang6Ni Tang7Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, the Second Affiliated Hospital, Chongqing Medical UniversityDepartment of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, the Second Affiliated Hospital, Chongqing Medical UniversityDepartment of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, the Second Affiliated Hospital, Chongqing Medical UniversityDepartment of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, the Second Affiliated Hospital, Chongqing Medical UniversityDepartment of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, the Second Affiliated Hospital, Chongqing Medical UniversityInstitute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University)Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, the Second Affiliated Hospital, Chongqing Medical UniversityDepartment of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, the Second Affiliated Hospital, Chongqing Medical UniversityAbstract The m6A methyltransferase METTL3 is a key regulator of RNA m6A modification, which plays a critical role in cancer development. Despite the significance of METTL3 in hepatocellular carcinoma (HCC), its post-translational modifications and their functional implications in HCC remain poorly understood. The present study reveals that METTL3 undergoes O-GlcNAcylation, which enhances its stability and promotes HCC progression. Specific O-GlcNAcylation sites (T186/S192/S193) in METTL3 are identified. O-GlcNAc modification reduces METTL3 ubiquitination, thereby increasing protein stability, and enhances its interaction with WTAP, thereby sustaining m6A levels in hepatoma cells. Notably, METTL3 O-GlcNAcylation upregulates the expression of minichromosome maintenance protein 10 (MCM10) by stabilizing its mRNA via an m6A-IGF2BP3-dependent manner. Targeting METTL3 O-GlcNAcylation with designed peptides effectively inhibits HCC growth both in vitro and in vivo. Collectively, our findings provide insights into the regulatory role of O-GlcNAcylation in modulating the m6A epitranscriptome and suggest the potential therapeutic relevance of targeting METTL3 O-GlcNAcylation in HCC.https://doi.org/10.1038/s41419-025-07844-1 |
| spellingShingle | Zhen Chen Jiaxin Yin Zhongqi Feng Yanlai Zhang Li Liang Xiaojun Wang Kai Wang Ni Tang O-GlcNAcylation of METTL3 drives hepatocellular carcinoma progression by upregulating MCM10 expression in an m6A-IGF2BP3-dependent manner Cell Death and Disease |
| title | O-GlcNAcylation of METTL3 drives hepatocellular carcinoma progression by upregulating MCM10 expression in an m6A-IGF2BP3-dependent manner |
| title_full | O-GlcNAcylation of METTL3 drives hepatocellular carcinoma progression by upregulating MCM10 expression in an m6A-IGF2BP3-dependent manner |
| title_fullStr | O-GlcNAcylation of METTL3 drives hepatocellular carcinoma progression by upregulating MCM10 expression in an m6A-IGF2BP3-dependent manner |
| title_full_unstemmed | O-GlcNAcylation of METTL3 drives hepatocellular carcinoma progression by upregulating MCM10 expression in an m6A-IGF2BP3-dependent manner |
| title_short | O-GlcNAcylation of METTL3 drives hepatocellular carcinoma progression by upregulating MCM10 expression in an m6A-IGF2BP3-dependent manner |
| title_sort | o glcnacylation of mettl3 drives hepatocellular carcinoma progression by upregulating mcm10 expression in an m6a igf2bp3 dependent manner |
| url | https://doi.org/10.1038/s41419-025-07844-1 |
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