CircVPS8 promotes the malignant phenotype and inhibits ferroptosis of glioma stem cells by acting as a scaffold for MKRN1, SOX15 and HNF4A

• Published in: Oncogene 2024-08, Vol.43 (36), p.2679-2695
• Main Authors: Hu, Jinpeng, Li, Xinqiao, Xu, Kai, Chen, Junhua, Zong, Shengliang, Zhang, Haiying, Li, Hao, Zhang, Guoqing, Guo, Zhengting, Zhao, Xiang, Jiang, Yang, Jing, Zhitao
• Format: Article
• Language: English
• Subjects: 13/1; 13/100; 13/109; 13/51; 14/19; 14/28; 38/77; 631/337/384; 631/67/1922; 82/29; Animals; Apoptosis; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell Biology; Cell Line, Tumor; Cell Proliferation; Circular RNA; Ferroptosis; Ferroptosis - genetics; Gene Expression Regulation, Neoplastic; Glioblastoma; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Glioma; Glioma - genetics; Glioma - metabolism; Glioma - pathology; Glioma cells; Hepatocyte nuclear factor 4; Hepatocyte Nuclear Factor 4 - genetics; Hepatocyte Nuclear Factor 4 - metabolism; Human Genetics; Humans; Internal Medicine; Medicine; Medicine & Public Health; Mice; Mice, Nude; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oncology; Phenotype; Phenotypes; RNA, Circular - genetics; SOXC Transcription Factors - genetics; SOXC Transcription Factors - metabolism; Stem cells; Therapeutic applications; Therapeutic targets; Ubiquitination
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-024-03116-y

Exciting breakthroughs have been achieved in the field of glioblastoma with therapeutic interventions targeting specific ferroptosis targets. Nonetheless, the precise mechanisms through which circRNAs regulate the ferroptosis pathway have yet to be fully elucidated. Here we have identified a novel circRNA, circVPS8, which is highly expressed in glioblastoma. Our findings demonstrated that circVPS8 enhances glioma stem cells’ viability, proliferation, sphere-forming ability, and stemness. Additionally, it inhibits ferroptosis in GSCs. In vivo, experiments further supported the promotion of glioblastoma growth by circVPS8. Mechanistically, circVPS8 acts as a scaffold, binding to both MKRN1 and SOX15, thus facilitating the ubiquitination of MKRN1 and subsequent degradation of SOX15. Due to competitive binding, the ubiquitination ability of MKRN1 towards HNF4A is reduced, leading to elevated HNF4A expression. Increased HNF4A expression, along with decreased SOX15 expression, synergistically inhibits ferroptosis in glioblastoma. Overall, our study highlights circVPS8 as a promising therapeutic target and provides valuable insights for clinically targeted therapy of glioblastoma.