Department of Neurosurgery, The First Hospital of China Medical University, NO.155 North Nanjing Street, Shenyang, Liaoning, 110001, China.
Department of Neurosurgery, The Central Hospital of Dalian University of Technology, Dalian, Liaoning, 116000, China.
Oncogene. 2024 Aug;43(36):2679-2695. doi: 10.1038/s41388-024-03116-y. Epub 2024 Aug 4.
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.
在针对特定铁死亡靶点的治疗干预措施方面，胶质母细胞瘤领域取得了令人兴奋的突破。然而，circRNAs 调节铁死亡途径的确切机制仍未完全阐明。在这里，我们鉴定了一种新型 circRNA，circVPS8，它在胶质母细胞瘤中高度表达。我们的研究结果表明，circVPS8 增强了神经胶质瘤干细胞的活力、增殖、球体形成能力和干性。此外，它还抑制了 GSCs 中的铁死亡。在体内实验中，进一步支持了 circVPS8 促进胶质母细胞瘤生长的作用。在机制上，circVPS8 作为一种支架，与 MKRN1 和 SOX15 结合，从而促进 MKRN1 的泛素化和 SOX15 的随后降解。由于竞争性结合，MKRN1 对 HNF4A 的泛素化能力降低，导致 HNF4A 表达升高。HNF4A 表达增加和 SOX15 表达减少协同抑制胶质母细胞瘤中的铁死亡。总之，我们的研究强调了 circVPS8 作为一种有前途的治疗靶点，并为胶质母细胞瘤的临床靶向治疗提供了有价值的见解。
