METTL3 promotes intrahepatic cholangiocarcinoma progression by regulating IFIT2 expression in an m6A-YTHDF2-dependent manner

N6-methyladenosine (m 6 A) RNA methylation has recently been found involving in regulatory mechanism of the tumor progression. Our aim was to explore the biological function and clinical significance of the m 6 A methyltransferase METTL3 in intrahepatic cholangiocarcinoma (ICC). In this study, we re...

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Bibliographic Details
Published in:Oncogene 2022-03, Vol.41 (11), p.1622-1633
Main Authors: Xu, Qiong-Cong, Tien, Yi-Chih, Shi, Yin-Hao, Chen, Siyun, Zhu, Ying-Qin, Huang, Xi-Tai, Huang, Chen-Song, Zhao, Wei, Yin, Xiao-Yu
Format: Article
Language:English
Subjects:
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Apoptosis
Cell Biology
Cholangiocarcinoma
Human Genetics
Internal Medicine
Medical prognosis
Medicine
Medicine & Public Health
Methylation
Methyltransferase
mRNA turnover
N6-methyladenosine
Oncology
Patients
Prognosis
RNA modification
Transcription activation
Tumors
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Summary:N6-methyladenosine (m 6 A) RNA methylation has recently been found involving in regulatory mechanism of the tumor progression. Our aim was to explore the biological function and clinical significance of the m 6 A methyltransferase METTL3 in intrahepatic cholangiocarcinoma (ICC). In this study, we revealed that METTL3 was upregulated and predicted poor prognosis of patients with ICC. Multivariate regression analysis demonstrated that METTL3 expression was an independent predictor for overall survival in patients with ICC. Moreover, METTL3 knockdown inhibited ICC progression, while METTL3 overexpression showed the opposite effect. METTL3 inhibitor STM2457 also showed anti-tumor effect in ICC. Mechanistically, METTL3 transcription was driven by H3K4me3 activation. Upregulation of METTL3 mediated m 6 A modification of IFIT2 mRNA and accelerated IFIT2 mRNA decay in a YTHDF2-dependent manner, which promoted the development of ICC and lead to poorer prognosis. In summary, our findings revealed that H3K4me3 activation-driven METTL 3 transcription promotes ICC progression by YTHDF2-mediated IFIT2 mRNA degradation, suggesting that METTL3 may serve as a potential target for human ICC therapy.
ISSN:0950-9232
1476-5594
DOI:10.1038/s41388-022-02185-1