N.sup.6-methyladenosine demethylase ALKBH5 suppresses malignancy of esophageal cancer by regulating microRNA biogenesis and RAI1 expression

N.sup.6-Methyladenosine (m.sup.6A) is the most prevalent epigenetic RNA modification and is vital in regulating malignancies. The roles of m.sup.6A modifiers on noncoding RNAs have not been fully investigated in esophageal cancer. By screening all m.sup.6A modifiers, ALKBH5 was the most potent membe...

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Bibliographic Details
Published in:Oncogene 2021-09, Vol.40 (37)
Main Authors: Chen, Pengxiang, Li, Song, Zhang, Ke, Zhao, Renchang, Cui, Jianfeng, Zhou, Wei, Liu, Yuchen, Zhang, Lin, Cheng, Yufeng
Format: Article
Language:English
Subjects:
Biosynthesis
Cancer
Care and treatment
Epigenetic inheritance
Esophageal cancer
Genetic aspects
Genetic regulation
Health aspects
Methyltransferases
MicroRNA
Oncology, Experimental
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Summary:N.sup.6-Methyladenosine (m.sup.6A) is the most prevalent epigenetic RNA modification and is vital in regulating malignancies. The roles of m.sup.6A modifiers on noncoding RNAs have not been fully investigated in esophageal cancer. By screening all m.sup.6A modifiers, ALKBH5 was the most potent member related to patient outcomes and suppressing esophageal cancer malignancy in cell and animal models. It demethylated pri-miR-194-2 and inhibited miR-194-2 biogenesis through an m.sup.6A/DGCR8-dependent manner. RAI1, previously considered as a circadian clock transcriptional regulator, was the main target of miR-194-2. It enhanced transcription of Hippo pathway upstream genes by binding to their 3'UTR and suppressed YAP/TAZ nuclear translocation. The ALKBH5/miR-194-2/RAI1 axis was also validated in clinical samples. In addition, the increased malignancy by low ALKBH5 was abolished by the YAP inhibitor verteporfin. Our findings uncover a critical role of ALKBH5 in miRNAs biogenesis and provide novel insight for developing treatment strategies in esophageal cancer.
ISSN:0950-9232
DOI:10.1038/s41388-021-01966-4