ALKBH5 suppresses gastric cancer tumorigenesis and metastasis by inhibiting the translation of uncapped WRAP53 RNA isoforms in an m6A-dependent manner
Abstract The N6-methyladenosine (m6A) modification serves as an essential epigenetic regulator in eukaryotic cells, playing a significant role in tumorigenesis and cancer progression. However, the detailed biological functions and underlying mechanisms of m6A regulation in gastric cancer (GC) are po...
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| Format: | Article |
| Language: | English |
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BMC
2025-01-01
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| Series: | Molecular Cancer |
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| Online Access: | https://doi.org/10.1186/s12943-024-02223-4 |
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| author | Ziqi Zheng Feizhi Lin Baiwei Zhao Guoming Chen Chengzhi Wei Xiaojiang Chen Runcong Nie Ruopeng Zhang Zhoukai Zhao Zhiwei Zhou Yuanfang Li Weigang Dai Yijia Lin Yongming Chen |
| author_facet | Ziqi Zheng Feizhi Lin Baiwei Zhao Guoming Chen Chengzhi Wei Xiaojiang Chen Runcong Nie Ruopeng Zhang Zhoukai Zhao Zhiwei Zhou Yuanfang Li Weigang Dai Yijia Lin Yongming Chen |
| author_sort | Ziqi Zheng |
| collection | DOAJ |
| description | Abstract The N6-methyladenosine (m6A) modification serves as an essential epigenetic regulator in eukaryotic cells, playing a significant role in tumorigenesis and cancer progression. However, the detailed biological functions and underlying mechanisms of m6A regulation in gastric cancer (GC) are poorly understood. Our research revealed that the m6A demethylase ALKBH5 was markedly downregulated in GC tissues, which was associated with poor patient prognosis. Functional studies demonstrated that suppressing ALKBH5 expression enhanced GC cell proliferation, migration, and invasion. Mechanistically, ALKBH5 removed m6A modifications from the 5’ uncapped and polyadenylated transcripts (UPTs) of WRAP53. This demethylation decreased WRAP53 stability and translation efficiency. The lower level of WRAP53 disrupts the interaction between USP6 and RALBP1 protein, promoting RALBP1 degradation and thereby suppressing the PI3K/Akt/mTOR signaling cascade, ultimately attenuating the progression of GC. These findings highlight the pivotal role of ALKBH5-mediated m6A demethylation in inhibiting GC progression and the potential role of ALKBH5 as a promising biomarker and therapeutic target for GC intervention. |
| format | Article |
| id | doaj-art-232c4ba2e75444f2b176a2eb7925026b |
| institution | Kabale University |
| issn | 1476-4598 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj-art-232c4ba2e75444f2b176a2eb7925026b2025-01-19T12:12:35ZengBMCMolecular Cancer1476-45982025-01-0124111910.1186/s12943-024-02223-4ALKBH5 suppresses gastric cancer tumorigenesis and metastasis by inhibiting the translation of uncapped WRAP53 RNA isoforms in an m6A-dependent mannerZiqi Zheng0Feizhi Lin1Baiwei Zhao2Guoming Chen3Chengzhi Wei4Xiaojiang Chen5Runcong Nie6Ruopeng Zhang7Zhoukai Zhao8Zhiwei Zhou9Yuanfang Li10Weigang Dai11Yijia Lin12Yongming Chen13Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Gastric Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Gastric Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Gastric Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Gastric Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Gastric Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Gastric Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Gastric Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Gastric Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Gastric Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Gastric Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterCenter of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen UniversityDepartment of General Surgery (Gastrointestinal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen UniversityDepartment of Gastric Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterAbstract The N6-methyladenosine (m6A) modification serves as an essential epigenetic regulator in eukaryotic cells, playing a significant role in tumorigenesis and cancer progression. However, the detailed biological functions and underlying mechanisms of m6A regulation in gastric cancer (GC) are poorly understood. Our research revealed that the m6A demethylase ALKBH5 was markedly downregulated in GC tissues, which was associated with poor patient prognosis. Functional studies demonstrated that suppressing ALKBH5 expression enhanced GC cell proliferation, migration, and invasion. Mechanistically, ALKBH5 removed m6A modifications from the 5’ uncapped and polyadenylated transcripts (UPTs) of WRAP53. This demethylation decreased WRAP53 stability and translation efficiency. The lower level of WRAP53 disrupts the interaction between USP6 and RALBP1 protein, promoting RALBP1 degradation and thereby suppressing the PI3K/Akt/mTOR signaling cascade, ultimately attenuating the progression of GC. These findings highlight the pivotal role of ALKBH5-mediated m6A demethylation in inhibiting GC progression and the potential role of ALKBH5 as a promising biomarker and therapeutic target for GC intervention.https://doi.org/10.1186/s12943-024-02223-4Gastric cancerMetastasisALKBH5M6AWRAP53 |
| spellingShingle | Ziqi Zheng Feizhi Lin Baiwei Zhao Guoming Chen Chengzhi Wei Xiaojiang Chen Runcong Nie Ruopeng Zhang Zhoukai Zhao Zhiwei Zhou Yuanfang Li Weigang Dai Yijia Lin Yongming Chen ALKBH5 suppresses gastric cancer tumorigenesis and metastasis by inhibiting the translation of uncapped WRAP53 RNA isoforms in an m6A-dependent manner Molecular Cancer Gastric cancer Metastasis ALKBH5 M6A WRAP53 |
| title | ALKBH5 suppresses gastric cancer tumorigenesis and metastasis by inhibiting the translation of uncapped WRAP53 RNA isoforms in an m6A-dependent manner |
| title_full | ALKBH5 suppresses gastric cancer tumorigenesis and metastasis by inhibiting the translation of uncapped WRAP53 RNA isoforms in an m6A-dependent manner |
| title_fullStr | ALKBH5 suppresses gastric cancer tumorigenesis and metastasis by inhibiting the translation of uncapped WRAP53 RNA isoforms in an m6A-dependent manner |
| title_full_unstemmed | ALKBH5 suppresses gastric cancer tumorigenesis and metastasis by inhibiting the translation of uncapped WRAP53 RNA isoforms in an m6A-dependent manner |
| title_short | ALKBH5 suppresses gastric cancer tumorigenesis and metastasis by inhibiting the translation of uncapped WRAP53 RNA isoforms in an m6A-dependent manner |
| title_sort | alkbh5 suppresses gastric cancer tumorigenesis and metastasis by inhibiting the translation of uncapped wrap53 rna isoforms in an m6a dependent manner |
| topic | Gastric cancer Metastasis ALKBH5 M6A WRAP53 |
| url | https://doi.org/10.1186/s12943-024-02223-4 |
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