GCN5-ERK lactylation-phosphorylation loop amplifies lactate-driven cancer progression

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• The Warburg effect increases lactate production, promoting cancer progression through unclear mechanisms.
• Lactate's role in cancer progression necessitates understanding its molecular drivers.

Purpose of the Study:

• To elucidate the molecular mechanism linking lactate to cancer progression.
• To identify key enzymes and pathways involved in lactate-mediated cancer growth.
• To develop and test a therapeutic strategy targeting this pathway.

Main Methods:

• Investigated the role of lactate in activating the MAPK pathway.
• Identified GCN5 as the lactyltransferase for ERK (Extracellular signal-regulated kinases).
• Assessed the impact of ERK lactylation on ERK-MEK interactions and activation.
• Developed and tested a cell-penetrating peptide inhibitor of ERK lactylation in cancer models.

Main Results:

• Lactate activates the MAPK pathway via ERK lactylation, promoting cancer progression.
• GCN5 was identified as the lactyltransferase responsible for ERK lactylation.
• Activated ERK phosphorylates GCN5, creating a positive feedback loop.
• ERK lactylation at K231 weakens ERK-MEK interaction, enhancing ERK dimerization and activation.
• The developed peptide inhibitor impaired tumor growth in KRAS-mutant cancer models.

Conclusions:

• Lactate accelerates cancer progression via an ERK-GCN5 lactylation-phosphorylation cascade.
• Targeting ERK lactylation presents a potential therapeutic strategy for RAS-ERK-driven cancers.