The m6A Methylation-Regulated AFF4 Promotes Self-Renewal of Bladder Cancer Stem Cells
The dynamic N6-methyladenosine (m6A) modification of mRNA plays a role in regulating gene expression and determining cell fate. However, the functions of m6A mRNA modification in bladder cancer stem cells (BCSCs) have not been described. Here, we show that global RNA m6A abundance and the expression...
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| Format: | Article |
| Language: | English |
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Wiley
2020-01-01
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| Series: | Stem Cells International |
| Online Access: | http://dx.doi.org/10.1155/2020/8849218 |
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| author | Qian Gao Jin Zheng Zegui Ni Pengli Sun Congcong Yang Maosheng Cheng Mingqing Wu Xiuhong Zhang Lin Yuan Yingyin Zhang Yang Li |
| author_facet | Qian Gao Jin Zheng Zegui Ni Pengli Sun Congcong Yang Maosheng Cheng Mingqing Wu Xiuhong Zhang Lin Yuan Yingyin Zhang Yang Li |
| author_sort | Qian Gao |
| collection | DOAJ |
| description | The dynamic N6-methyladenosine (m6A) modification of mRNA plays a role in regulating gene expression and determining cell fate. However, the functions of m6A mRNA modification in bladder cancer stem cells (BCSCs) have not been described. Here, we show that global RNA m6A abundance and the expression of m6A-forming enzyme METTL3 are higher in BCSCs than those in non-CSCs of bladder cancer (BCa) cells. The depletion of the METTL3 inhibited the self-renewal of BCSCs, as evidenced by decreased ALDH activity and sphere-forming ability. Mechanistically, METTL3 regulates the m6A modification and thereby the expression of AF4/FMR2 family member 4 (AFF4), knockdown of which phenocopies the METTL3 ablation and diminishes the tumor-initiating capability of BCSCs in vivo. AFF4 binds to the promoter regions and sustains the transcription of SOX2 and MYC which have critical biological functions in BCSCs. Collectively, our results demonstrate the critical roles of m6A modification in self-renewal and tumorigenicity of BCSCs through a novel signaling axis of METTL3-AFF4-SOX2/MYC. |
| format | Article |
| id | doaj-art-b2cf8582c8da4f1286adc27b0f808391 |
| institution | Kabale University |
| issn | 1687-966X 1687-9678 |
| language | English |
| publishDate | 2020-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Stem Cells International |
| spelling | doaj-art-b2cf8582c8da4f1286adc27b0f8083912025-02-03T01:05:01ZengWileyStem Cells International1687-966X1687-96782020-01-01202010.1155/2020/88492188849218The m6A Methylation-Regulated AFF4 Promotes Self-Renewal of Bladder Cancer Stem CellsQian Gao0Jin Zheng1Zegui Ni2Pengli Sun3Congcong Yang4Maosheng Cheng5Mingqing Wu6Xiuhong Zhang7Lin Yuan8Yingyin Zhang9Yang Li10Department of Genetics, School of Life Science, Anhui Medical University, Hefei, Anhui 230031, ChinaDepartment of Pathology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, No. 100 Hai Ning Road, Hongkou District, Shanghai 200080, ChinaDepartment of Genetics, School of Life Science, Anhui Medical University, Hefei, Anhui 230031, ChinaDepartment of Genetics, School of Life Science, Anhui Medical University, Hefei, Anhui 230031, ChinaDepartment of Genetics, School of Life Science, Anhui Medical University, Hefei, Anhui 230031, ChinaDepartment of Genetics, School of Life Science, Anhui Medical University, Hefei, Anhui 230031, ChinaDepartment of Genetics, School of Life Science, Anhui Medical University, Hefei, Anhui 230031, ChinaDepartment of Genetics, School of Life Science, Anhui Medical University, Hefei, Anhui 230031, ChinaDepartment of Pathology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, No. 100 Hai Ning Road, Hongkou District, Shanghai 200080, ChinaDepartment of Genetics, School of Life Science, Anhui Medical University, Hefei, Anhui 230031, ChinaDepartment of Genetics, School of Life Science, Anhui Medical University, Hefei, Anhui 230031, ChinaThe dynamic N6-methyladenosine (m6A) modification of mRNA plays a role in regulating gene expression and determining cell fate. However, the functions of m6A mRNA modification in bladder cancer stem cells (BCSCs) have not been described. Here, we show that global RNA m6A abundance and the expression of m6A-forming enzyme METTL3 are higher in BCSCs than those in non-CSCs of bladder cancer (BCa) cells. The depletion of the METTL3 inhibited the self-renewal of BCSCs, as evidenced by decreased ALDH activity and sphere-forming ability. Mechanistically, METTL3 regulates the m6A modification and thereby the expression of AF4/FMR2 family member 4 (AFF4), knockdown of which phenocopies the METTL3 ablation and diminishes the tumor-initiating capability of BCSCs in vivo. AFF4 binds to the promoter regions and sustains the transcription of SOX2 and MYC which have critical biological functions in BCSCs. Collectively, our results demonstrate the critical roles of m6A modification in self-renewal and tumorigenicity of BCSCs through a novel signaling axis of METTL3-AFF4-SOX2/MYC.http://dx.doi.org/10.1155/2020/8849218 |
| spellingShingle | Qian Gao Jin Zheng Zegui Ni Pengli Sun Congcong Yang Maosheng Cheng Mingqing Wu Xiuhong Zhang Lin Yuan Yingyin Zhang Yang Li The m6A Methylation-Regulated AFF4 Promotes Self-Renewal of Bladder Cancer Stem Cells Stem Cells International |
| title | The m6A Methylation-Regulated AFF4 Promotes Self-Renewal of Bladder Cancer Stem Cells |
| title_full | The m6A Methylation-Regulated AFF4 Promotes Self-Renewal of Bladder Cancer Stem Cells |
| title_fullStr | The m6A Methylation-Regulated AFF4 Promotes Self-Renewal of Bladder Cancer Stem Cells |
| title_full_unstemmed | The m6A Methylation-Regulated AFF4 Promotes Self-Renewal of Bladder Cancer Stem Cells |
| title_short | The m6A Methylation-Regulated AFF4 Promotes Self-Renewal of Bladder Cancer Stem Cells |
| title_sort | m6a methylation regulated aff4 promotes self renewal of bladder cancer stem cells |
| url | http://dx.doi.org/10.1155/2020/8849218 |
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