SMYD2 induced PGC1α methylation promotes stemness maintenance of glioblastoma stem cells.

IF 16.4 1区医学 Q1 CLINICAL NEUROLOGY Neuro-oncology Pub Date : 2024-09-05 DOI:10.1093/neuonc/noae090

Mengdie Li, Zhixiang Zhang, Liuguijie He, Xiefeng Wang, Jianxing Yin, Xiuxing Wang, Yongping You, Xu Qian, Xin Ge, Zhumei Shi

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Abstract

Background: The high fatality rate of glioblastoma (GBM) is attributed to glioblastoma stem cells (GSCs), which exhibit heterogeneity and therapeutic resistance. Metabolic plasticity of mitochondria is the hallmark of GSCs. Targeting mitochondrial biogenesis of GSCs is crucial for improving clinical prognosis in GBM patients.

Methods: SMYD2-induced PGC1α methylation and followed nuclear export are confirmed by co-immunoprecipitation, cellular fractionation, and immunofluorescence. The effects of SMYD2/PGC1α/CRM1 axis on GSCs mitochondrial biogenesis are validated by oxygen consumption rate, ECAR, and intracranial glioma model.

Results: PGC1α methylation causes the disabled mitochondrial function to maintain the stemness, thereby enhancing the radio-resistance of GSCs. SMYD2 drives PGC1α K224 methylation (K224me), which is essential for promoting the stem-like characteristics of GSCs. PGC1α K224me is preferred binding with CRM1, accelerating PGC1α nuclear export and subsequent dysfunction. Targeting PGC1α methylation exhibits significant radiotherapeutic efficacy and prolongs patient survival.

Conclusions: These findings unveil a novel regulatory pathway involving mitochondria that govern stemness in GSCs, thereby emphasizing promising therapeutic strategies targeting PGC1α and mitochondria for the treatment of GBM.

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SMYD2诱导的PGC1α甲基化促进胶质母细胞瘤干细胞的干性维持。

背景：胶质母细胞瘤（GBM）的高致死率归因于胶质母细胞瘤干细胞（GSCs），它们表现出异质性和耐药性。线粒体的代谢可塑性是 GSCs 的特征。靶向 GSCs 的线粒体生物生成对于改善 GBM 患者的临床预后至关重要：方法：通过共免疫沉淀、细胞分馏和免疫荧光证实了SMYD2诱导的PGC1α甲基化和随后的核输出。通过OCR、ECAR和颅内胶质瘤模型验证了SMYD2/PGC1α/CRM1轴对GSCs线粒体生物生成的影响：结果：PGC1α甲基化导致线粒体功能失效，无法维持干性，从而增强了GSCs的放射抗性。SMYD2驱动PGC1α K224甲基化（K224me），这对促进GSCs的干样特性至关重要。PGC1α K224me优先与CRM1结合，加速了PGC1α的核输出和随后的功能障碍。以PGC1α甲基化为靶点可显著提高放疗疗效，延长患者生存期：这些发现揭示了一条涉及线粒体的新型调控途径，该途径控制着GSCs的干性，从而强调了针对PGC1α和线粒体的治疗策略在治疗GBM方面的前景。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

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.