Targeting the METTL3/YTHDF3/m6A/PGK1 axis to combat Choriocarcinoma progression

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Choriocarcinoma (CC) is an aggressive tumor with poorly understood metabolic regulation.
• Glycolysis is vital for cancer growth, and Phosphoglycerate kinase 1 (PGK1) is a key enzyme within this pathway.
• N6-methyladenosine (m6A) RNA methylation is implicated in tumorigenesis, but its role in CC and specifically with PGK1 is uninvestigated.

Purpose of the Study:

• To investigate the role of m6A-modified PGK1 in choriocarcinoma (CC) progression.
• To elucidate the regulatory mechanism of PGK1 by m6A modification in CC.
• To identify PGK1 as a potential diagnostic biomarker and therapeutic target for CC.

Main Methods:

• Bioinformatics analysis to identify key regulators in CC progression and glycolysis.
• In vitro experiments involving PGK1 knockdown in CC cell lines (BeWo, JEG-3).
• In vivo studies using xenograft mouse models to assess tumor growth inhibition.
• Investigation of the roles of methyltransferase-like 3 (METTL3) and YTH domain-containing family protein 3 (YTHDF3) in PGK1 regulation.

Main Results:

• Bioinformatics identified PGK1 as a key regulator in CC progression and glycolysis, with upregulation observed in CC cell lines.
• PGK1 knockdown suppressed CC cell proliferation, glycolysis, and tumor growth in vivo.
• The METTL3/YTHDF3 axis was found to enhance CC progression by increasing PGK1 mRNA stability via m6A modification and promoting its translation.
• METTL3 or YTHDF3 overexpression partially rescued the effects of PGK1 silencing, restoring PGK1 expression and glycolytic function.

Conclusions:

• The METTL3/YTHDF3/m6A/PGK1 pathway significantly promotes choriocarcinoma progression by stabilizing PGK1 mRNA and enhancing glycolysis.
• PGK1 serves as a crucial mediator of CC tumorigenesis and represents a potential diagnostic biomarker.
• Targeting the METTL3/YTHDF3/m6A/PGK1 axis presents a promising therapeutic strategy for choriocarcinoma treatment.