1. YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma.
- Author
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Hou, Jiajie, Zhang, He, Liu, Jun, Zhao, Zhenjun, Wang, Jianye, Lu, Zhike, Hu, Bian, Zhou, Jiankui, Zhao, Zhicong, Feng, Mingxuan, Zhang, Haiyan, Shen, Bin, Huang, Xingxu, Sun, Beicheng, He, Chuan, and Xia, Qiang
- Subjects
LIQUID chromatography-mass spectrometry ,HEPATOCELLULAR carcinoma ,FUEL - Abstract
Background: Dynamic N
6 -methyladenosine (m6 A) modification was previously identified as a ubiquitous post-transcriptional regulation that affected mRNA homeostasis. However, the m6 A-related epitranscriptomic alterations and functions remain elusive in human cancer. Here we aim to identify the profile and outcome of m6 A-methylation in hepatocellular carcinoma (HCC). Results: Using liquid chromatography-tandem mass spectrometry and m6 A-immunoprecipitation in combination with high-throughput sequencing, we determined the m6 A-mRNA levels in human HCC. Human HCC exhibited a characteristic gain of m6 A modification in tandem with an increase of mRNA expression, owing to YTH domain family 2 (YTHDF2) reduction. The latter predicted poor classification and prognosis of HCC patients, and highly correlated with HCC m6 A landscape. YTHDF2 silenced in human HCC cells or ablated in mouse hepatocytes provoked inflammation, vascular reconstruction and metastatic progression. Mechanistically, YTHDF2 processed the decay of m6 A-containing interleukin 11 (IL11) and serpin family E member 2 (SERPINE2) mRNAs, which were responsible for the inflammation-mediated malignancy and disruption of vascular normalization. Reciprocally, YTHDF2 transcription succumbed to hypoxia-inducible factor-2α (HIF-2α). Administration of a HIF-2α antagonist (PT2385) restored YTHDF2-programed epigenetic machinery and repressed liver cancer. Conclusion: Our results have characterized the m6 A-mRNA landscape in human HCC and revealed YTHDF2 as a molecular 'rheostat' in epitranscriptome and cancer progression. [ABSTRACT FROM AUTHOR]- Published
- 2019
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