SMYD2 诱导 PGC1α 甲基化促进神经胶质瘤干细胞干性维持。

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

机构信息

Department of Nutrition and Food Hygiene, Center for Global Health, School of Public Health, Jiangsu Key Lab of Cancer Biomarkers, Prevention, and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.

National Health Commission Key Laboratory of Antibody Techniques, Department of Cell Biology, Jiangsu Provincial Key Laboratory of Human Functional Genomics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.

出版信息

Neuro Oncol. 2024 Sep 5;26(9):1587-1601. doi: 10.1093/neuonc/noae090.

DOI:10.1093/neuonc/noae090

PMID:38721826

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11376450/

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.

摘要

背景

胶质母细胞瘤（GBM）的高死亡率归因于胶质母细胞瘤干细胞（GSCs），其表现出异质性和治疗耐药性。线粒体的代谢可塑性是 GSCs 的标志。靶向 GSCs 的线粒体生物发生对于改善 GBM 患者的临床预后至关重要。

方法

通过共免疫沉淀、细胞分级分离和免疫荧光证实 SMYD2 诱导的 PGC1α 甲基化和随后的核输出。通过耗氧量、ECAR 和颅内神经胶质瘤模型验证 SMYD2/PGC1α/CRM1 轴对 GSCs 线粒体生物发生的影响。

结果

PGC1α 甲基化导致线粒体功能障碍，从而维持干细胞特性，从而增强 GSCs 的放射抗性。SMYD2 驱动 PGC1α K224 甲基化（K224me），这对于促进 GSCs 的干细胞样特征至关重要。PGC1α K224me 优先与 CRM1 结合，加速 PGC1α 核输出和随后的功能障碍。靶向 PGC1α 甲基化显示出显著的放射治疗效果，并延长了患者的生存时间。