Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou 215006, China; Department of Neurosurgery, Xinghua People's Hospital Affiliated to Yangzhou University, Xinghua 225700, China.
Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou 215006, China.
Neoplasia. 2024 Nov;57:101055. doi: 10.1016/j.neo.2024.101055. Epub 2024 Sep 10.
Glioblastoma (GBM) poses a significant medical challenge due to its aggressive nature and poor prognosis. Mitochondrial unfolded protein response (UPRmt) and the heat shock factor 1 (HSF1) pathway play crucial roles in GBM pathogenesis. Post-translational modifications, such as SUMOylation, regulate the mechanism of action of HSF1 and may influence the progression of GBM. Understanding the interplay between SUMOylation-modified HSF1 and GBM pathophysiology is essential for developing targeted therapies.
We conducted a comprehensive investigation using cellular, molecular, and in vivo techniques. Cell culture experiments involved establishing stable cell lines, protein extraction, Western blotting, co-immunoprecipitation, and immunofluorescence analysis. Mass spectrometry was utilized for protein interaction studies. Computational modeling techniques were employed for protein structure analysis. Plasmid construction and lentiviral transfection facilitated the manipulation of HSF1 SUMOylation. In vivo studies employed xenograft models for tumor growth assessment.
Our research findings indicate that HSF1 primarily undergoes SUMOylation at the lysine residue K298, enhancing its nuclear translocation, stability, and downstream heat shock protein expression, while having no effect on its trimer conformation. SUMOylated HSF1 promoted the UPRmt pathway, leading to increased GBM cell proliferation, migration, invasion, and reduced apoptosis. In vivo studies have confirmed that SUMOylation of HSF1 enhances its oncogenic effect in promoting tumor growth in GBM xenograft models.
This study elucidates the significance of SUMOylation modification of HSF1 in driving GBM progression. Targeting SUMOylated HSF1 may offer a novel therapeutic approach for GBM treatment. Further investigation into the specific molecular mechanisms influenced by SUMOylated HSF1 is warranted for the development of effective targeted therapies to improve outcomes for GBM patients.
由于其侵袭性和预后不良，胶质母细胞瘤（GBM）是一个重大的医学挑战。线粒体未折叠蛋白反应（UPRmt）和热休克因子 1（HSF1）途径在 GBM 的发病机制中起着关键作用。翻译后修饰，如 SUMO 化，调节 HSF1 的作用机制，并可能影响 GBM 的进展。了解 SUMO 化修饰的 HSF1 与 GBM 病理生理学之间的相互作用对于开发靶向治疗至关重要。
我们使用细胞、分子和体内技术进行了全面的研究。细胞培养实验包括建立稳定的细胞系、蛋白质提取、Western blot、共免疫沉淀和免疫荧光分析。质谱用于蛋白质相互作用研究。计算建模技术用于蛋白质结构分析。质粒构建和慢病毒转染促进了 HSF1 SUMO 化的操作。体内研究采用异种移植模型评估肿瘤生长。
我们的研究结果表明，HSF1 主要在赖氨酸残基 K298 处发生 SUMO 化，增强其核转位、稳定性和下游热休克蛋白表达，而对其三聚体构象没有影响。SUMO 化的 HSF1 促进 UPRmt 途径，导致 GBM 细胞增殖、迁移、侵袭增加，凋亡减少。体内研究证实，HSF1 的 SUMO 化增强了其在促进 GBM 异种移植模型肿瘤生长中的致癌作用。
本研究阐明了 HSF1 SUMO 化修饰在驱动 GBM 进展中的重要性。靶向 SUMO 化的 HSF1 可能为 GBM 治疗提供一种新的治疗方法。进一步研究 SUMO 化的 HSF1 影响的特定分子机制对于开发有效的靶向治疗方法以改善 GBM 患者的预后是必要的。
