Abstract
BackgroundDynamic N6-methyladenosine (m6A) modification was previously identified as a ubiquitous post-transcriptional 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 m6A-methylation in hepatocellular carcinoma (HCC).ResultsUsing 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.ConclusionOur results have characterized the m6A-mRNA landscape in human HCC and revealed YTHDF2 as a molecular ‘rheostat’ in epitranscriptome and cancer progression.
Highlights
Dynamic N6-methyladenosine (m6A) modification was previously identified as a ubiquitous posttranscriptional regulation that affected mRNA homeostasis
We further reveal a transcriptional inhibition of YTH domain family 2 (YTHDF2) by HIF2α, which has been therapeutically targeted in renal cell carcinoma and hepatocellular carcinoma (HCC) [29, 30]
To assess the global m6A-methylation in HCC, we examined 37 tumor paired with adjacent non-tumor samples
Summary
Dynamic N6-methyladenosine (m6A) modification was previously identified as a ubiquitous posttranscriptional regulation that affected mRNA homeostasis. 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 [1,2,3]. Another demethylase ALKBH5 (a-ketoglutarate-dependent dioxygenase alkB homolog 5) tends to stabilize stem-cellrelated transcripts [6, 7]. Diverse post-transcriptional outcomes of m6A-methylation rely on its readers, which are poorly understood in human cancers.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
