YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma
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RESEARCH
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YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma Jiajie Hou1,2,3,4*†, He Zhang1,5†, Jun Liu6†, Zhenjun Zhao1, Jianye Wang1, Zhike Lu6, Bian Hu7, Jiankui Zhou7, Zhicong Zhao1, Mingxuan Feng1, Haiyan Zhang4,8, Bin Shen9, Xingxu Huang7, Beicheng Sun2, Chuan He6,10* and Qiang Xia1*
Abstract Background: Dynamic N6-methyladenosine (m6A) modification was previously identified as a ubiquitous posttranscriptional regulation that affected mRNA homeostasis. However, the m6A-related epitranscriptomic alterations and functions remain elusive in human cancer. Here we aim to identify the profile and outcome of m6Amethylation in hepatocellular carcinoma (HCC). Results: Using liquid chromatography-tandem mass spectrometry and m6A-immunoprecipitation in combination with high-throughput sequencing, we determined the m6A-mRNA levels in human HCC. Human HCC exhibited a characteristic gain of m6A 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 m6A 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 m6A-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 m6A-mRNA landscape in human HCC and revealed YTHDF2 as a molecular ‘rheostat’ in epitranscriptome and cancer progression. Keywords: m6A, YTHDF2, HCC, Inflammation, Vessel normalization, IL-11, Serpin E2, HIF-2α antagonism
Background As the most frequent internal decoration on eukaryotic mRNAs, N6-methyladenosine (m6A) has been proven to play fundamental roles in regulating gene expression and biological processes [1–3]. Pioneering studies have offered a glimpse into the sophisticated mechanisms of reversible m6A modification in cancer. The demethylase FTO (fat * Correspondence: [email protected]; [email protected]; [email protected] † Jiajie Hou, He Zhang and Jun Liu contributed equally to this work. 1 Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China 6 Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA Full list of author information is available at the end of the article
mass-and obesity-associated protein) decreases global m6A levels, leading to either downregulation of tumor suppressor genes or upregulation of tumor promoter genes [4, 5]. Another d
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