Longstanding evidence implicates glioma stem cells (GSCs) 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 demonstrated that global lactylation was significantly elevated in GSCs compared to differentiated glioma cells (DGCs). 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 its 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.

中文翻译：

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PTBP1 乳酸化通过 PFKFB4 驱动的糖酵解促进神经胶质瘤干细胞维持


长期证据表明，神经胶质瘤干细胞 （GSC） 是神经胶质瘤增殖和复发的主要驱动因素。GSC 具有独特的代谢景观，其特征是糖酵解升高。糖酵解活性增强导致的乳酸积累可以驱动赖氨酸乳酸化以调节蛋白质功能，这表明阐明 GSC 中的乳酸化景观可以为神经胶质瘤生物学提供见解。在此，我们证明与分化的神经胶质瘤细胞 （DGC） 相比，GSC 的整体乳酸化显着升高。PTBP1 是 RNA 加工的中心调节因子，在 GSC 中高乳酸化，SIRT1 诱导 PTBP1 脱乳。PTBP1-K436 乳酸化支持胶质瘤进展和 GSC 维持。从机制上讲，K436 乳酰化通过减弱与 TRIM21 的相互作用来抑制 PTBP1 蛋白酶体降解。此外，PTBP1 乳酰化增强了其 RNA 结合能力并促进了 PFKFB4 mRNA 的稳定，从而进一步增加了糖酵解。总之，这些发现揭示了 GSC 中由代谢重编程驱动的乳酰化介导的机制，该机制诱导异常的表观遗传修饰以进一步刺激糖酵解，从而导致加剧肿瘤发生的恶性循环。