Funding
National Natural Science Foundation of China (NSFC)
Postdoctoral Innovation Project of Shandong Province (山东省博士后创新专项基金)
Taishan Scholar Foundation of Shandong Province (山东省泰山学者特聘教授)
Taishan Scholar Project of Shandong Province
Central Government Guiding Local Science and Technology Development Foundation of Shandong Province
National Key Research and Development Program of China (NKPs)
Science and Technology Support Plan for Youth Innovation of Colleges and Universities of Shandong Province of China (山东省高等学校青年创新团队发展计划)
ARTICLE ABSTRACT
Long-standing evidence implicates glioma stem cells (GSC) as the major driver for glioma propagation and recurrence. GSCs have a distinctive metabolic landscape characterized by elevated glycolysis. Lactate accumulation resulting from enhanced glycolytic activity can drive lysine lactylation to regulate protein functions, suggesting that elucidating the lactylation landscape in GSCs could provide insights into glioma biology. Herein, we have demonstrated that global lactylation was significantly elevated in GSCs compared with differentiated glioma cells. Polypyrimidine tract–binding protein 1 (PTBP1), a central regulator of RNA processing, was hyperlactylated in GSCs, and SIRT1 induced PTBP1 delactylation. PTBP1-K436 lactylation supported glioma progression and GSC maintenance. Mechanistically, K436 lactylation inhibited PTBP1 proteasomal degradation by attenuating the interaction with TRIM21. Moreover, PTBP1 lactylation enhanced RNA-binding capacity and facilitated PFKFB4 mRNA stabilization, which further increased glycolysis. Together, these findings uncovered a lactylation-mediated mechanism in GSCs driven by metabolic reprogramming that induces aberrant epigenetic modifications to further stimulate glycolysis, resulting in a vicious cycle to exacerbate tumorigenesis.Significance: Glycolysis-induced lactylation enhances the function of PTBP1 to promote glioma stem cell maintenance, indicating that PTBP1 lactylation could be a potential target for the development of innovative glioma therapies.
