Lactate-associated H3K18 Lactylation and SYT8 in the Temozolomide Response of Glioblastoma Cells

IF 4.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Molecular Biology Pub Date : 2027-01-01 Epub Date: 2026-10-12 DOI:10.1016/j.jmb.2026.170064

Sansong Chen, Yiming Deng, Limin Cheng

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引用次数: 0

Abstract

Lactate and histone H3K18 lactylation (H3K18la) have been linked to glioblastoma biology. We examined their relationship with synaptotagmin 8 (SYT8) and the response to temozolomide (TMZ). U251MG and U87MG cells were cultured under normoxia or hypoxia and exposed to TMZ, sodium lactate or both. H3K18la enrichment at the SYT8 promoter was assessed by chromatin immunoprecipitation. The effects of SYT8 knockdown were evaluated using CCK-8, colony formation, flow cytometry, wound healing and Transwell assays. Lactate and protein abundance were measured, including H3K18la normalized to total H3 in the four-group experiment. Endpoint tumor weight was assessed in a subcutaneous U87MG xenograft model. TMZ reduced CCK-8 signal and intracellular lactate in both cell lines, whereas lactate supplementation attenuated several effects of TMZ. H3K18la was enriched at the SYT8 promoter, and SYT8 knockdown was accompanied by lower lactate and H3K18la signals. Under TMZ treatment, SYT8-depleted cells formed fewer colonies and had a higher apoptosis fraction. Lactate partly reversed these changes and increased H3K18la/total H3 while SYT8 protein remained low. The combined SYT8-knockdown and TMZ group had the lowest endpoint tumor weight. These results link SYT8 to lactate-associated H3K18 lactylation and TMZ response in GBM cells. The reciprocal changes in SYT8, lactate and H3K18la suggest a possible feedback relationship that warrants further mechanistic study.

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乳酸相关H3K18乳酸化和SYT8在胶质母细胞瘤细胞替莫唑胺反应中的作用。

乳酸和组蛋白H3K18乳酸化（H3K18la）与胶质母细胞瘤生物学有关。我们研究了它们与synaptotagmin 8 （SYT8）和对替莫唑胺（TMZ）的反应的关系。U251MG和U87MG细胞分别在常氧或缺氧条件下培养，并分别暴露于TMZ、乳酸钠或两者同时暴露。通过染色质免疫沉淀法评估SYT8启动子处H3K18la的富集情况。通过CCK-8、菌落形成、流式细胞术、伤口愈合和Transwell试验评估SYT8敲除的效果。测定乳酸和蛋白质丰度，包括四组实验中归一化到总H3的H3K18la。在皮下U87MG异种移植模型中评估终点肿瘤重量。TMZ降低了两种细胞系的CCK-8信号和细胞内乳酸，而乳酸补充减弱了TMZ的一些作用。H3K18la在SYT8启动子富集，SYT8敲低伴随着乳酸和H3K18la信号的降低。在TMZ处理下，syt8缺失的细胞形成更少的集落，凋亡率更高。乳酸部分逆转了这些变化，增加了H3K18la/总H3，而SYT8蛋白保持在较低水平。syt8 -敲除联合TMZ组的终点肿瘤重量最低。这些结果将SYT8与GBM细胞中乳酸相关的H3K18乳酸化和TMZ反应联系起来。SYT8、乳酸和H3K18la的相互变化表明可能存在反馈关系，值得进一步的机制研究。

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来源期刊

Journal of Molecular Biology 生物-生化与分子生物学

CiteScore

11.30

自引率

1.80%

发文量

412

审稿时长

28 days

期刊介绍： Journal of Molecular Biology (JMB) provides high quality, comprehensive and broad coverage in all areas of molecular biology. The journal publishes original scientific research papers that provide mechanistic and functional insights and report a significant advance to the field. The journal encourages the submission of multidisciplinary studies that use complementary experimental and computational approaches to address challenging biological questions. Research areas include but are not limited to: Biomolecular interactions, signaling networks, systems biology; Cell cycle, cell growth, cell differentiation; Cell death, autophagy; Cell signaling and regulation; Chemical biology; Computational biology, in combination with experimental studies; DNA replication, repair, and recombination; Development, regenerative biology, mechanistic and functional studies of stem cells; Epigenetics, chromatin structure and function; Gene expression; Membrane processes, cell surface proteins and cell-cell interactions; Methodological advances, both experimental and theoretical, including databases; Microbiology, virology, and interactions with the host or environment; Microbiota mechanistic and functional studies; Nuclear organization; Post-translational modifications, proteomics; Processing and function of biologically important macromolecules and complexes; Molecular basis of disease; RNA processing, structure and functions of non-coding RNAs, transcription; Sorting, spatiotemporal organization, trafficking; Structural biology; Synthetic biology; Translation, protein folding, chaperones, protein degradation and quality control.