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Oncogene. 2019 Jun;38(24):4755-4772. doi: 10.1038/s41388-019-0755-0. Epub 2019 Feb 22.

Dynamic m6A mRNA methylation reveals the role of METTL3-m6A-CDCP1 signaling axis in chemical carcinogenesis.

Author information

1
Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
2
Department of Physiology, Zunyi Medical College, Guizhou, 563000, China.
3
Guangdong Key Laboratory of Urology, Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510230, China.
4
The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510080, China.
5
Department of Preventive Medicine, The School of Medicine, Jinan University, Guangzhou, 510632, China.
6
Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China. wang.min@yale.edu.
7
Department of Pathology and the Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, 06519, USA. wang.min@yale.edu.
8
Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China. linshb6@mail.sysu.edu.cn.
9
Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China. jiweidong@mail.sysu.edu.cn.

Abstract

N6-methyladenosine (m6A) is the most abundant internal modification in mammalian mRNAs. Despite its functional importance in various physiological events, the role of m6A in chemical carcinogenesis remains largely unknown. Here we profiled the dynamic m6A mRNA modification during cellular transformation induced by chemical carcinogens and identified a subset of cell transformation-related, concordantly modulated m6A sites. Notably, the increased m6A in 3'-UTR mRNA of oncogene CDCP1 was found in malignant transformed cells. Mechanistically, the m6A methyltransferase METTL3 and demethylases ALKBH5 mediate the m6A modification in 3'-UTR of CDCP1 mRNA. METTL3 and m6A reader YTHDF1 preferentially recognize m6A residues on CPCP1 3'-UTR and promote CDCP1 translation. We further showed that METTL3 and CDCP1 are upregulated in the bladder cancer patient samples and the expression of METTL3 and CDCP1 is correlated with the progression status of the bladder cancers. Inhibition of the METTL3-m6A-CDCP1 axis resulted in decreased growth and progression of chemical-transformed cells and bladder cancer cells. Most importantly, METTL3-m6A-CDCP1 axis has synergistic effect with chemical carcinogens in promoting malignant transformation of uroepithelial cells and bladder cancer tumorigenesis in vitro and in vivo. Taken together, our results identify dynamic m6A modification in chemical-induced malignant transformation and provide insight into critical roles of the METTL3-m6A-CDCP1 axis in chemical carcinogenesis.

PMID:
30796352
DOI:
10.1038/s41388-019-0755-0

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