Unveiling the impact of SUMOylation at K298 site of heat shock factor 1 on glioblastoma malignant progression

• Published in: Neoplasia (New York, N.Y.) Vol. 57; p. 101055
• Main Authors: Li, Xiang, Wang, Zongqi, Gao, Bixi, Dai, Kun, Wu, Jiang, Shen, Kecheng, Li, Guangzhao, Niu, Xiaowang, Wu, Xin, Li, Longyuan, Shen, Haitao, Li, Haiying, Yu, Zhengquan, Wang, Zhong, Chen, Gang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2024; Neoplasia Press; Elsevier
• Subjects: Animals; Apoptosis; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Models, Animal; Disease Progression; Glioblastoma; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Heat shock factor 1; Heat shock protein 60; Heat Shock Transcription Factors - genetics; Heat Shock Transcription Factors - metabolism; Humans; Mice; Mitochondrial heat shock protein 70; Mitochondrial unfolded protein response; Original Research; SUMOylation; Unfolded Protein Response; Xenograft Model Antitumor Assays; Mitochondrial heat shock protein 70; Heat shock protein 60; SUMOylation; Heat shock factor 1; Mitochondrial unfolded protein response; Glioblastoma
• ISSN: 1476-5586; 1522-8002; 1476-5586
• DOI: 10.1016/j.neo.2024.101055

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. [Display omitted]