METTL3-mediated m6A modification of ZBTB4 mRNA is involved in the smoking-induced EMT in cancer of the lung

• Main Authors: Cheng Cheng (Author), Yan Wu (Author), Tian Xiao (Author), Junchao Xue (Author), Jing Sun (Author), Haibo Xia (Author), Huimin Ma (Author), Lu Lu (Author), Junjie Li (Author), Aimin Shi (Author), Tao Bian (Author), Qizhan Liu (Author)
• Format: Book
• Published: Elsevier, 2021-03-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

N6-methyladenosine (m6A) is an epigenetic modification associated with various tumors, but its role in tumorigenesis remains unexplored. Here, as confirmed by methylated RNA immunoprecipitation sequencing (meRIP-seq) and RNA sequencing (RNA-seq) analyses, exposure of human bronchial epithelial (HBE) cells to cigarette smoke extract (CSE) caused an m6A modification in the 3' UTR of ZBTB4, a transcriptional repressor. For these cells, CSE also elevated methyltransferase-like 3 (METTL3) levels, which increased the m6A modification of ZBTB4. RIP-qPCR illustrated that ZBTB4 was the intent gene of YTHDF2 and that levels of ZBTB4 were decreased in an YTHDF2-dependent mechanism. The lower levels of ZBTB4 were associated with upregulation of EZH2, which enhanced H3K27me3 combining with E-cadherin promoter, causing lower E-cadherin levels and induction of the epithelial-mesenchymal transition (EMT). Further, in the lungs of mice, downregulation of METTL3 alleviated the cigarette smoke (CS)-induced EMT. Further, the expression of METTL3 was high in the lung tissues of smokers and inversely correlated with ZBTB4. Overall, our results show that the METTL3-mediated m6A modification of ZBTB4 via EZH2 is involved in the CS-induced EMT and in lung cancer. These results indicate that m6A modifications are a potential therapeutic target of lung damage induced by CS.

Item Description

2162-2531
10.1016/j.omtn.2020.12.001