ACAT1-mediated METTL3 acetylation inhibits cell migration and invasion in triple negative breast cancer

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited therapeutic options.
• Acetylation is a crucial post-translational modification impacting cancer progression.
• Understanding acetylation-related mechanisms is vital for developing novel TNBC treatments.

Purpose of the Study:

• To elucidate the role of acetylation in triple-negative breast cancer (TNBC) progression.
• To investigate the functional relationship between acetyl-CoA acetyltransferase 1 (ACAT1) and methyltransferase like-3 (METTL3) in TNBC.
• To identify upstream regulators of the ACAT1/METTL3 axis in TNBC.

Main Methods:

• Quantitative polymerase chain reaction (qPCR) and western blot to assess METTL3 expression.
• Co-Immunoprecipitation (Co-IP) and GST pulldown assays to confirm ACAT1-METTL3 interaction.
• Immunoprecipitation (IP) assays to determine ACAT1's role in METTL3 stabilization.
• Functional assays to evaluate the impact of the NR2F6/ACAT1/METTL3 axis on TNBC cell migration and invasion.

Main Results:

• Methyltransferase like-3 (METTL3) was downregulated in TNBC cells.
• Acetyl-CoA acetyltransferase 1 (ACAT1) interacts with and stabilizes METTL3 by inhibiting its ubiquitin-proteasome degradation.
• ACAT1 significantly inhibits TNBC cell migration and invasion.
• Nuclear receptor subfamily 2 group F member 6 (NR2F6) transcriptionally upregulates ACAT1 expression.
• The NR2F6/ACAT1/METTL3 axis was demonstrated to suppress TNBC cell migration and invasion.

Conclusions:

• NR2F6 transcriptionally activates ACAT1, which in turn stabilizes METTL3.
• The NR2F6/ACAT1/METTL3 pathway exerts suppressive effects on TNBC cell migration and invasion.
• This study reveals a novel acetylation-related mechanism critical for TNBC progression.