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, Wei Zhao*

*Corresponding author for this work

Research output: Contribution to journalArticle

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5785-5798
Number of pages14
JournalCancer Research
Volume79
Issue number22
DOIs
StatePublished - Nov 15 2019

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Li, F., Yi, Y., Miao, Y., Long, W., Long, T., Chen, S., Cheng, W., Zou, C., Zheng, Y., Wu, X., Ding, J., Zhu, K., Chen, D., Xu, Q., Wang, J., Liu, Q., Zhi, F., Ren, J., Cao, Q., & Zhao, W. (2019). N6-methyladenosine modulates nonsense-mediated mRNA decay in human glioblastoma. Cancer Research, 79(22), 5785-5798. https://doi.org/10.1158/0008-5472.CAN-18-2868