GDH1催化谷氨酰胺分解反馈激活表皮生长因子受体/PI3K/AKT通路,重新规划胶质母细胞瘤的新陈代谢。

IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Neuro-oncology Pub Date : 2024-10-24 DOI:10.1093/neuonc/noae222
Rui Yang, Guanghui Zhang, Zhen Meng, Li Wang, Yanping Li, Haibin Li, Siyuan Yan, Xiaonan Wei, Shanshan Wang, Hongjuan Cui
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引用次数: 0

摘要

背景:谷氨酰胺是癌细胞生长的重要营养物质,它为核酸和脂肪酸的合成提供了生物来源,但谷氨酰胺酵解在信号转导和胶质母细胞瘤(GBM)进展中的作用仍鲜为人知:方法:通过敲除和过表达细胞来探索 GDH1 在细胞增殖、肿瘤形成和有氧糖酵解中的功能作用。通过RNA-seq、染色质免疫沉淀、荧光素酶检测和Western印迹,验证了谷氨酸脱氢酶1(GDH1,又称GLUD1)和KDM6A对表皮生长因子受体-AKT通路的调控作用。我们还进行了代谢物水平测定和海马测定,以评估 GHD1 在糖酵解重编程中的功能作用:结果:在此,我们报告了 GDH1 催化谷氨酰胺酵解对 GBM 细胞系的增殖和脑肿瘤的发生至关重要,即使在高葡萄糖条件下也是如此。谷氨酰胺通过谷氨酰胺分解代谢产生α-酮戊二酸(α-KG)。我们证明,谷氨酰胺与亮氨酸结合可通过增强谷氨酰胺分解和α-KG的产生来激活哺乳动物的TORC1。α-KG通过减少抑制性组蛋白修饰H3K27me3来增加PDPK1的转录,然后促进PI3K/AKT/mTOR通路的激活。α-KG诱导的这种转录激活需要组蛋白去甲基化酶KDM6A,而KDM6A是一种2-氧代戊二酸加氧酶,在将α-KG转化为琥珀酸的过程中发挥着重要作用。此外,我们还发现 GDH1 催化的谷氨酰胺酵解也会增加 HK2 的表达,并在高葡萄糖条件下促进糖酵解,这依赖于 KDM6A 介导的 H3K27 去甲基化:这些发现表明谷氨酰胺酵解在调节信号转导和代谢重编程方面具有新的功能,为谷氨酰胺酵解在 GBM 进展中的独特作用提供了进一步的证据。
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GDH1-catalytic glutaminolysis feedback activate EGFR/PI3K/AKT pathway and reprogram glioblastoma metabolism.

Background: Glutamine is an important nutriment for cancer cell growth that provides biological sources for nucleic acid and fatty acid synthesis, but the role of glutaminolysis in signal transduction and glioblastoma (GBM) progression remains little known.

Methods: Knockdown and overexpression cells were obtained to explore the functional roles of GDH1 in cell proliferation, tumor formation and aerobic glycolysis. RNA-seq, Chromatin immunoprecipitation, luciferase assay and western blot were performed to verify the regulation of EGFR-AKT pathway by the glutamate dehydrogenase 1 (GDH1, also known as GLUD1) and KDM6A. Metabolite-level measurements and Seahorse Assay were performed to assess the functional role of GHD1 in reprogramming glycolysis.

Results: Here, we report that GDH1 catalytic glutaminolysis is essential for GBM cell line proliferation and brain tumorigenesis even in high-glucose conditions. Glutamine is metabolized through glutaminolysis to produce α-ketoglutarate (α-KG). We demonstrate that glutamine in combination with leucine activates mammalian TORC1 by enhancing glutaminolysis and α-KG production. α-KG increases the transcription of PDPK1 by reducing the suppressive histone modification H3K27me3, and then promotes the activation of PI3K/AKT/mTOR pathway. This transcriptional activation induced by α-KG requires histone demethylase KDM6A, which is a 2-oxoglutarate oxygenase that plays important roles in converting α-KG to succinate. Furthermore, we show that GDH1-catalytic glutaminolysis also increases the expression of HK2 and promotes glycolysis in high-glucose condition dependent on KDM6A-mediated demethylation of H3K27.

Conclusion: These findings suggest a novel function of glutaminolysis in regulation of signal transduction and metabolism reprograming, provide further evidence for unique role of glutaminolysis in GBM progression.

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来源期刊
Neuro-oncology
Neuro-oncology 医学-临床神经学
CiteScore
27.20
自引率
6.30%
发文量
1434
审稿时长
3-8 weeks
期刊介绍: Neuro-Oncology, the official journal of the Society for Neuro-Oncology, has been published monthly since January 2010. Affiliated with the Japan Society for Neuro-Oncology and the European Association of Neuro-Oncology, it is a global leader in the field. The journal is committed to swiftly disseminating high-quality information across all areas of neuro-oncology. It features peer-reviewed articles, reviews, symposia on various topics, abstracts from annual meetings, and updates from neuro-oncology societies worldwide.
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