Targeting the SIN1 mediated TTK/LDHA-H3K18la-GLUT3 Axis Disrupts Metabolic-Epigenetic Crosstalk and Suppresses Progression in Hyperglycolytic Breast Cancer - PubMed
4 days ago
- #Histone Lactylation
- #Metabolic Reprogramming
- #Breast Cancer
- SIN1 is identified as a central node in highly invasive breast cancer tumors, co-enriched with epithelial-mesenchymal transition and proliferation programs.
- SIN1 scaffolds TTK to promote phosphorylation of LDHA at Tyr239, amplifying glycolysis and lactate production.
- Lactate accumulation increases histone H3K18 lactylation (H3K18la), which upregulates GLUT3, enhancing glucose uptake and creating a self-reinforcing loop.
- LR-90 is identified as a small-molecule inhibitor of the SIN1/TTK/LDHA complex, reducing p-LDHA��239, lactate levels, and tumor growth.
- Elevated SIN1 expression is clinically associated with adverse pathological features and inferior overall survival in breast cancer patients.
- Targeting the SIN1-mediated axis with LR-90, alone or combined with chemotherapy, may offer a therapeutic strategy for high-glycolytic breast cancer.