The m6A methyltransferase METTL3 promotes bladder cancer progression via AFF4/NF-κB/MYC signaling network

N 6 -methyladenosine (m6A) is the most abundant modification in eukaryotic messenger RNAs (mRNAs), and plays important roles in many bioprocesses. However, its functions in bladder cancer (BCa) remain elusive. Here, we discovered that methyltransferase-like 3 (METTL3), a major RNA N 6 -adenosine met...

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Published in:Oncogene Vol. 38; no. 19; pp. 3667 - 3680
Main Authors: Cheng, Maosheng, Sheng, Lu, Gao, Qian, Xiong, Qiuchan, Zhang, Haojie, Wu, Mingqing, Liang, Yu, Zhu, Fengyu, Zhang, Yingyin, Zhang, Xiuhong, Yuan, Quan, Li, Yang
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 09.05.2019
Nature Publishing Group
Subjects:
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13/89
13/95
38/39
45/91
631/208/176
631/67/589/1336
64/60
96/63
Adenosine
Apoptosis
Bladder cancer
Cell Biology
Cell growth
Cell proliferation
Cell survival
DNA-directed RNA polymerase
Gene expression
Human Genetics
Internal Medicine
Medicine
Medicine & Public Health
Myc protein
N6-methyladenosine
NF-κB protein
Oncology
Polymerase chain reaction
Ribonucleic acid
RNA
Tumorigenicity
ISSN:0950-9232, 1476-5594, 1476-5594
Online Access:Get full text
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Summary:N 6 -methyladenosine (m6A) is the most abundant modification in eukaryotic messenger RNAs (mRNAs), and plays important roles in many bioprocesses. However, its functions in bladder cancer (BCa) remain elusive. Here, we discovered that methyltransferase-like 3 (METTL3), a major RNA N 6 -adenosine methyltransferase, was significantly up-regulated in human BCa. Knockdown of METTL3 drastically reduced BCa cell proliferation, invasion, and survival in vitro and tumorigenicity in vivo. On the other hand, overexpression of METTL3 significantly promoted BCa cell growth and invasion. Through transcriptome sequencing, m 6 A sequencing and m 6 A methylated RNA immuno-precipitation quantitative reverse-transcription polymerase chain reaction, we revealed the profile of METTL3-mediated m 6 A modification in BCa cells for the first time. AF4/FMR2 family member 4 ( AFF4 ), two key regulators of NF-κB pathway ( IKBKB and RELA ) and MYC were further identified as direct targets of METTL3-mediated m 6 A modification. In addition, we showed that besides NF-κB, AFF4 binds to the promoter of MYC and promotes its expression, implying a novel multilevel regulatory network downstream of METTL3. Our results uncovered an AFF4/NF-κB/MYC signaling network operated by METTL3-mediated m6A modification and provided insight into the mechanisms of BCa progression.
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ISSN:0950-9232
1476-5594
1476-5594
DOI:10.1038/s41388-019-0683-z