FTO mediated ERBB2 demethylation promotes tumor progression in esophageal squamous cell carcinoma cells

Area of Science:

• Molecular Biology
• Cancer Research
• Epigenetics

Background:

• N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic messenger RNA.
• The precise role of m6A modifications in gene expression regulation, particularly in cancer, requires further elucidation.

Purpose of the Study:

• To investigate the role of the mRNA demethylase FTO in esophageal squamous cell carcinoma (ESCC).
• To identify FTO targets and understand the underlying molecular mechanisms in ESCC progression.

Main Methods:

• In vitro MeRIP-seq and RNA-seq assays were employed to analyze m6A modification and gene expression.
• Transcriptome-wide m6A-seq and RNA-seq were used to identify FTO targets.
• Loss and gain functional studies were conducted to assess the roles of FTO, YTHDF1, and ERBB2.

Main Results:

• FTO was significantly upregulated in ESCC tissues and cells.
• FTO knockdown suppressed ESCC cell proliferation, migration, and invasion.
• ERBB2 was identified as a direct target of FTO, contributing to ESCC tumorigenesis and metastasis.
• The m6A reader YTHDF1 stabilizes ERBB2 mRNA through m6A modification, forming a regulatory cascade.

Conclusions:

• A novel signaling cascade involving FTO, YTHDF1, and ERBB2 finely regulates ESCC progression.
• Targeting this FTO-YTHDF1-ERBB2 axis presents a potential therapeutic strategy for ESCC.