YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma

Area of Science:

• Epitranscriptomics
• Cancer Biology
• Molecular Oncology

Background:

• N6-methyladenosine (m6A) is a key epitranscriptomic modification regulating mRNA homeostasis.
• The role of m6A alterations in human cancer, particularly hepatocellular carcinoma (HCC), remains largely uncharacterized.

Purpose of the Study:

• To identify the m6A-mRNA profile and its clinical significance in HCC.
• To elucidate the functional role of m6A regulators in HCC pathogenesis.

Main Methods:

• Liquid chromatography-tandem mass spectrometry (LC-MS/MS)
• m6A-immunoprecipitation sequencing (m6A-IP-seq)
• Analysis of YTH domain family 2 (YTHDF2) expression and function in HCC cells and mouse models.
• Investigation of the interplay between YTHDF2, hypoxia-inducible factor-2α (HIF-2α), and target genes.

Main Results:

• Human HCC exhibits altered m6A modification patterns and increased mRNA expression, linked to reduced YTHDF2 levels.
• Decreased YTHDF2 expression correlates with poor HCC patient prognosis and promotes inflammation, vascular reconstruction, and metastasis.
• YTHDF2 regulates the decay of IL11 and SERPINE2 mRNAs, contributing to malignancy and vascular disruption.
• YTHDF2 transcription is suppressed by HIF-2α; HIF-2α inhibition restores YTHDF2 function and represses HCC.

Conclusions:

• The study characterizes the m6A landscape in HCC, identifying YTHDF2 as a critical regulator.
• YTHDF2 acts as a molecular rheostat controlling epitranscriptomic alterations and cancer progression in HCC.
• Targeting the HIF-2α/YTHDF2 axis presents a potential therapeutic strategy for HCC.