OXCT1 promotes triple negative breast cancer immune escape via modulating succinylation modification of PGK1

Area of Science:

• Oncology
• Immunology
• Metabolism

Background:

• Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options.
• Aerobic glycolysis is a hallmark of cancer, contributing to tumor growth and immune evasion.
• The role of 3-oxoacid CoA-transferase 1 (OXCT1) in TNBC's metabolic reprogramming and immune escape remains unclear.

Purpose of the Study:

• To investigate the specific role of OXCT1 in promoting TNBC growth and immune escape.
• To elucidate the regulatory mechanism of OXCT1 in aerobic glycolysis-driven TNBC.
• To explore the relationship between OXCT1, phosphoglycerate kinase 1 (PGK1), and lysine methyltransferase 5A (KMT5A) in TNBC.

Main Methods:

• In vitro studies using TNBC cell lines and patient-derived organoids (PDOs).
• Manipulation of OXCT1 and KMT5A expression.
• Analysis of cell proliferation, lactic acid secretion, PD-L1 expression, and T-cell killing.
• Investigation of protein modifications (succinylation, ubiquitination) and histone methylation (H4K20me1).
• Correlation analysis with clinical TNBC samples.

Main Results:

• OXCT1 overexpression enhances TNBC cell proliferation and PD-L1 expression, effects reversed by 2-DG.
• OXCT1 interference in PDOs reduces tumor growth, lactic acid secretion, and increases T-cell killing.
• OXCT1 increases PGK1 protein stability via succinylation at K146, independent of PGK1 mRNA levels.
• KMT5A promotes OXCT1 expression by increasing H4K20me1 levels at the OXCT1 promoter.

Conclusions:

• OXCT1 plays a crucial role in promoting TNBC growth and immune escape by enhancing aerobic glycolysis.
• KMT5A-mediated histone methylation upregulates OXCT1 expression.
• OXCT1 stabilizes PGK1 through succinylation, further driving aerobic glycolysis and immune evasion in TNBC.
• Targeting OXCT1 presents a potential therapeutic strategy for TNBC.