ALKBH5-mediated N6-methyladenosine modification of TRERNA1 promotes DLBCL proliferation via p21 downregulation
Abstract Long noncoding RNAs (lncRNAs) have crucial functions in the tumorigenesis and metastasis of cancers. N6-methyladenosine (m6A) modification of RNA is an important epigenetic regulatory mechanism in various malignancies. Nevertheless, the mechanism of m6A-modified lncRNA in diffuse large B ce...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-01-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-022-00819-7 |
| _version_ | 1798026231006887936 |
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| author | Wei Song Fei Fei Fengchang Qiao Zuyi Weng Yuanxun Yang Bei Cao Jing Yue Jiaxuan Xu Meihong Zheng Juan Li |
| author_facet | Wei Song Fei Fei Fengchang Qiao Zuyi Weng Yuanxun Yang Bei Cao Jing Yue Jiaxuan Xu Meihong Zheng Juan Li |
| author_sort | Wei Song |
| collection | DOAJ |
| description | Abstract Long noncoding RNAs (lncRNAs) have crucial functions in the tumorigenesis and metastasis of cancers. N6-methyladenosine (m6A) modification of RNA is an important epigenetic regulatory mechanism in various malignancies. Nevertheless, the mechanism of m6A-modified lncRNA in diffuse large B cell lymphoma (DLBCL) has remained poorly defined. In the present study, we showed that lncRNA TRERNA1 was associated with the poor prognosis of DLBCL patients. TRERNA1 with internal m6A modification was highly correlated with the demethylase ALKBH5 expression. We further demonstrated that TRERNA1 was a potential downstream target of ALKBH5-mediated m6A modification by m6A-RNA sequencing and m6A-RIP assays. Decreased m6A methylation of TRERNA1 regulated by ALKBH5 was shown to regulate cell proliferation in vitro and in vivo. The results of mechanism analyses revealed that TRERNA1 recruited EZH2 to epigenetically silence the expression of the cyclin-dependent kinases inhibitor p21 by H3K27me3 modification of its promoter region. In addition, ALKBH5 further inhibited p21 expression. Taken together, our results elucidate the functional roles and epigenetic alterations of TRERNA1 through m6A modification in DLBCL. TRERNA1, the expression of which is upregulated by ALKBH5, acts as a scaffold that decreases p21 expression. The results of the present study provide novel targets for the diagnosis and treatment of DLBCL. |
| first_indexed | 2024-04-11T18:31:59Z |
| format | Article |
| id | doaj.art-5eb8fb62a3934acc9a0450dbdec98313 |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-04-11T18:31:59Z |
| publishDate | 2022-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-5eb8fb62a3934acc9a0450dbdec983132022-12-22T04:09:24ZengNature Publishing GroupCell Death Discovery2058-77162022-01-018111210.1038/s41420-022-00819-7ALKBH5-mediated N6-methyladenosine modification of TRERNA1 promotes DLBCL proliferation via p21 downregulationWei Song0Fei Fei1Fengchang Qiao2Zuyi Weng3Yuanxun Yang4Bei Cao5Jing Yue6Jiaxuan Xu7Meihong Zheng8Juan Li9Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical SchoolPhase I Clinical Trials Unit, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical SchoolWomen’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health care HospitalPhase I Clinical Trials Unit, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical SchoolPhase I Clinical Trials Unit, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical SchoolPhase I Clinical Trials Unit, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical SchoolDepartment of Gynaecology and Obstetrics, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical SchoolPhase I Clinical Trials Unit, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical SchoolPhase I Clinical Trials Unit, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical SchoolPhase I Clinical Trials Unit, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical SchoolAbstract Long noncoding RNAs (lncRNAs) have crucial functions in the tumorigenesis and metastasis of cancers. N6-methyladenosine (m6A) modification of RNA is an important epigenetic regulatory mechanism in various malignancies. Nevertheless, the mechanism of m6A-modified lncRNA in diffuse large B cell lymphoma (DLBCL) has remained poorly defined. In the present study, we showed that lncRNA TRERNA1 was associated with the poor prognosis of DLBCL patients. TRERNA1 with internal m6A modification was highly correlated with the demethylase ALKBH5 expression. We further demonstrated that TRERNA1 was a potential downstream target of ALKBH5-mediated m6A modification by m6A-RNA sequencing and m6A-RIP assays. Decreased m6A methylation of TRERNA1 regulated by ALKBH5 was shown to regulate cell proliferation in vitro and in vivo. The results of mechanism analyses revealed that TRERNA1 recruited EZH2 to epigenetically silence the expression of the cyclin-dependent kinases inhibitor p21 by H3K27me3 modification of its promoter region. In addition, ALKBH5 further inhibited p21 expression. Taken together, our results elucidate the functional roles and epigenetic alterations of TRERNA1 through m6A modification in DLBCL. TRERNA1, the expression of which is upregulated by ALKBH5, acts as a scaffold that decreases p21 expression. The results of the present study provide novel targets for the diagnosis and treatment of DLBCL.https://doi.org/10.1038/s41420-022-00819-7 |
| spellingShingle | Wei Song Fei Fei Fengchang Qiao Zuyi Weng Yuanxun Yang Bei Cao Jing Yue Jiaxuan Xu Meihong Zheng Juan Li ALKBH5-mediated N6-methyladenosine modification of TRERNA1 promotes DLBCL proliferation via p21 downregulation Cell Death Discovery |
| title | ALKBH5-mediated N6-methyladenosine modification of TRERNA1 promotes DLBCL proliferation via p21 downregulation |
| title_full | ALKBH5-mediated N6-methyladenosine modification of TRERNA1 promotes DLBCL proliferation via p21 downregulation |
| title_fullStr | ALKBH5-mediated N6-methyladenosine modification of TRERNA1 promotes DLBCL proliferation via p21 downregulation |
| title_full_unstemmed | ALKBH5-mediated N6-methyladenosine modification of TRERNA1 promotes DLBCL proliferation via p21 downregulation |
| title_short | ALKBH5-mediated N6-methyladenosine modification of TRERNA1 promotes DLBCL proliferation via p21 downregulation |
| title_sort | alkbh5 mediated n6 methyladenosine modification of trerna1 promotes dlbcl proliferation via p21 downregulation |
| url | https://doi.org/10.1038/s41420-022-00819-7 |
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