Dynamic 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).

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.

Our results have characterized the m⁶A-mRNA landscape in human HCC and revealed YTHDF2 as a molecular ‘rheostat’ in epitranscriptome and cancer progression.