PTBP1 Lactylation Promotes Glioma Stem Cell Maintenance through PFKFB4-Driven Glycolysis

IF 12.5 1区 医学 Q1 ONCOLOGY
Zijian Zhou, Xianyong Yin, Hao Sun, Jiaze Lu, Yuming Li, Yang Fan, Peiwen Lv, Min Han, Jing Wu, Shengjie Li, Zihao Liu, Hongbo Zhao, Haohan Sun, Hao Fan, Shan Wang, Tao Xin
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引用次数: 0

Abstract

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.
PTBP1 乳化作用通过 PFKFB4 驱动的糖酵解促进胶质瘤干细胞的维持
长期证据表明,胶质瘤干细胞(GSCs)是胶质瘤扩散和复发的主要驱动因素。神经胶质瘤干细胞具有独特的新陈代谢特征,其特点是糖酵解活动增强。糖酵解活性增强导致的乳酸积累可驱动赖氨酸乳化以调节蛋白质功能,这表明阐明GSCs的乳化景观可为胶质瘤生物学提供见解。在本文中,我们证实与分化胶质瘤细胞(DGCs)相比,GSCs 中的全局乳化作用明显升高。PTBP1是RNA加工的核心调控因子,在GSCs中乳化过度,SIRT1诱导PTBP1脱乳化。PTBP1-K436乳化支持胶质瘤的进展和GSC的维持。从机理上讲,K436乳化通过减弱与TRIM21的相互作用抑制了PTBP1蛋白酶体降解。此外,PTBP1乳酰化增强了其RNA结合能力,促进了PFKFB4 mRNA的稳定,从而进一步增加了糖酵解。这些发现共同揭示了一种乳化介导的 GSCs 代谢重编程机制,该机制可诱导异常表观遗传修饰,进一步刺激糖酵解,从而形成恶性循环,加剧肿瘤发生。
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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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