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Tumor Biology and Immunology

N6-Methyladenosine Modulates Nonsense-Mediated mRNA Decay in Human Glioblastoma

Fuxi Li, Yang Yi, Yanyan Miao, Wenyong Long, Teng Long, Siyun Chen, Weisheng Cheng, Changye Zou, Yueyuan Zheng, Xingui Wu, Junjun Ding, Kaiyu Zhu, Delin Chen, Qiongcong Xu, Jinkai Wang, Qing Liu, Feng Zhi, Jian Ren, Qi Cao and Wei Zhao
Fuxi Li
RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.Key Laboratory of Stem Cells and Tissue Engineering, Sun Yat-sen University, Ministry of Education, Guangzhou, China.
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Yang Yi
Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
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Yanyan Miao
State Key Laboratory of Oncology in South China, Cancer Center, Collaborative Innovation Center for Cancer Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
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Wenyong Long
Neurosurgery Department, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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Teng Long
RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.Key Laboratory of Stem Cells and Tissue Engineering, Sun Yat-sen University, Ministry of Education, Guangzhou, China.
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Siyun Chen
RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.Key Laboratory of Stem Cells and Tissue Engineering, Sun Yat-sen University, Ministry of Education, Guangzhou, China.
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Weisheng Cheng
Key Laboratory of Stem Cells and Tissue Engineering, Sun Yat-sen University, Ministry of Education, Guangzhou, China.
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Changye Zou
Musculoskeletal Oncology Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
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Yueyuan Zheng
State Key Laboratory of Oncology in South China, Cancer Center, Collaborative Innovation Center for Cancer Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
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Xingui Wu
Key Laboratory of Stem Cells and Tissue Engineering, Sun Yat-sen University, Ministry of Education, Guangzhou, China.
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Junjun Ding
Key Laboratory of Stem Cells and Tissue Engineering, Sun Yat-sen University, Ministry of Education, Guangzhou, China.
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Kaiyu Zhu
State Key Laboratory of Oncology in South China, Cancer Center, Collaborative Innovation Center for Cancer Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
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Delin Chen
RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.Key Laboratory of Stem Cells and Tissue Engineering, Sun Yat-sen University, Ministry of Education, Guangzhou, China.
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Qiongcong Xu
Department of Pancreatobiliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
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Jinkai Wang
RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.Key Laboratory of Stem Cells and Tissue Engineering, Sun Yat-sen University, Ministry of Education, Guangzhou, China.
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Qing Liu
Neurosurgery Department, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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Feng Zhi
Department of Neurosurgery, The First People's Hospital of Changzhou, Changzhou, Jiangsu, China.
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Jian Ren
State Key Laboratory of Oncology in South China, Cancer Center, Collaborative Innovation Center for Cancer Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
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Qi Cao
Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
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  • For correspondence: zhaowei23@mail.sysu.edu.cn qi.cao@northwestern.edu
Wei Zhao
RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.Key Laboratory of Stem Cells and Tissue Engineering, Sun Yat-sen University, Ministry of Education, Guangzhou, China.
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  • For correspondence: zhaowei23@mail.sysu.edu.cn qi.cao@northwestern.edu
DOI: 10.1158/0008-5472.CAN-18-2868 Published November 2019
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Abstract

The N6-methyladenosine (m6A) modification influences various mRNA metabolic events and tumorigenesis, however, its functions in nonsense-mediated mRNA decay (NMD) and whether NMD detects induced carcinogenesis pathways remain undefined. Here, we showed that the m6A methyltransferase METTL3 sustained its oncogenic role by modulating NMD of splicing factors and alternative splicing isoform switches in glioblastoma (GBM). Methylated RNA immunoprecipitation-seq (MeRIP-seq) analyses showed that m6A modification peaks were enriched at metabolic pathway–related transcripts in glioma stem cells (GSC) compared with neural progenitor cells. In addition, the clinical aggressiveness of malignant gliomas was associated with elevated expression of METTL3. Furthermore, silencing METTL3 or overexpressing dominant-negative mutant METTL3 suppressed the growth and self-renewal of GSCs. Integrated transcriptome and MeRIP-seq analyses revealed that downregulating the expression of METTL3 decreased m6A modification levels of serine- and arginine-rich splicing factors (SRSF), which led to YTHDC1-dependent NMD of SRSF transcripts and decreased SRSF protein expression. Reduced expression of SRSFs led to larger changes in alternative splicing isoform switches. Importantly, the phenotypes mediated by METTL3 deficiency could be rescued by downregulating BCL-X or NCOR2 isoforms. Overall, these results establish a novel function of m6A in modulating NMD and uncover the mechanism by which METTL3 promotes GBM tumor growth and progression.

Significance: These findings establish the oncogenic role of m6A writer METTL3 in glioblastoma stem cells.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Cancer Res 2019;79:5785–98

  • Received September 14, 2018.
  • Revision received January 10, 2019.
  • Accepted September 11, 2019.
  • Published first September 17, 2019.
  • ©2019 American Association for Cancer Research.
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Cancer Research: 79 (22)
November 2019
Volume 79, Issue 22
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N6-Methyladenosine Modulates Nonsense-Mediated mRNA Decay in Human Glioblastoma
Fuxi Li, Yang Yi, Yanyan Miao, Wenyong Long, Teng Long, Siyun Chen, Weisheng Cheng, Changye Zou, Yueyuan Zheng, Xingui Wu, Junjun Ding, Kaiyu Zhu, Delin Chen, Qiongcong Xu, Jinkai Wang, Qing Liu, Feng Zhi, Jian Ren, Qi Cao and Wei Zhao
Cancer Res November 15 2019 (79) (22) 5785-5798; DOI: 10.1158/0008-5472.CAN-18-2868

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N6-Methyladenosine Modulates Nonsense-Mediated mRNA Decay in Human Glioblastoma
Fuxi Li, Yang Yi, Yanyan Miao, Wenyong Long, Teng Long, Siyun Chen, Weisheng Cheng, Changye Zou, Yueyuan Zheng, Xingui Wu, Junjun Ding, Kaiyu Zhu, Delin Chen, Qiongcong Xu, Jinkai Wang, Qing Liu, Feng Zhi, Jian Ren, Qi Cao and Wei Zhao
Cancer Res November 15 2019 (79) (22) 5785-5798; DOI: 10.1158/0008-5472.CAN-18-2868
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