N6-Methyladenosine Modulates Nonsense-Mediated mRNA Decay in Human Glioblastoma
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 15, 2019
- Source ID
- 10.1158/0008-5472.can-18-2868
Entities
People
- Changye Zou
- Delin Chen
- Feng Zhi
- Fuxi Li
- Jian Ren
- Jin-kai Wang
- Junjun Ding
- Kaiyu Zhu
- Qi Cao
- Qing Liu
- Qiongcong Xu
- Siyun Chen
- Teng Long
- Wei Zhao
- Weisheng Cheng
- Wenyong Long
- Xingui Wu
- Yanyan Miao
- Yi Yang
- Yueyuan Zheng
Organizations
- American Cancer Society
- Central South University
- National Institutes of Health
- National Natural Science Foundation of China
- Northwestern University
- Sun Yat-sen University
- The First People's Hospital of Changzhou
- United States Department of Defense