南方医科大学学报2026，Vol.46Issue(6)：1290-1300,11.DOI:10.12122/j.issn.1673-4254.2026.06.09
ZEB2通过CYLD/FASN轴重编程脂质代谢促进胶质母细胞瘤进展
ZEB2 promotes glioblastoma progression by reprogramming lipid metabolism through the CYLD/FASN axis
摘要
Abstract
Objective To investigate the role of ZEB2 in lipid metabolic reprogramming of glioblastoma and its mechanism for promoting glioblastoma progression.Methods Mouse models bearing orthotopic intracranial xenografts derived from LN-229 and GBM007 cells with stable ZEB2 knockdown were used to assess tumor growth and mouse survival..Lipid droplet accumulation,lipid composition,and membrane fluidity in the cells with ZEB2 knockdown were examined using Nile Red staining,transmission electron microscopy,untargeted lipidomics,and fluorescence recovery after photobleaching(FRAP).The candidate mediators were screened by integrating RNA sequencing,fatty acid synthase(FASN)immunoprecipitation-mass spectrometry,and BioGRID interaction data.Promoter luciferase assays,ChIP-qPCR,promoter mutagenesis,co-immunoprecipitation,protein degradation pathway inhibition,and ubiquitination assays were performed to investigate the regulatory role of the ZEB2-CYLD-FASN axis.Results ZEB2 knockdown significantly suppressed intracranial glioblastoma growth and prolonged mouse survival.Glioblastoma cells with ZEB2 silencing showed reduced lipid droplet accumulation,decreased saturated fatty acid-associated storage lipids,increased phospholipid species containing polyunsaturated fatty acyl chains,and enhanced membrane fluidity.Mechanistically,ZEB2 knockdown reduced FASN protein abundance,whereas FASN restoration reversed lipid droplet reduction induced by ZEB2 silencing.Multi-omics screening identified CYLD as a key intermediate.ZEB2 was capable of directly binding to and activating the CYLD promoter.CYLD knockdown decreased FASN protein levels,whereas CYLD restoration recovered FASN abundance and lipid droplet formation.CYLD was co-localized and interacted with FASN.MG132 partially restored FASN abundance under ZEB2 knockdown,and CYLD overexpression reduced FASN ubiquitination.Conclusion ZEB2 promotes glioblastoma lipid metabolic reprogramming and tumor progression by transcriptionally activating CYLD,which maintains FASN protein stability at least in part through ubiquitination-associated regulation.关键词
胶质母细胞瘤/锌指E盒结合同源盒2/脂质代谢/脂肪酸合成酶/去泛素化酶Key words
glioblastoma/zinc finger E-box binding homeobox 2/lipid metabolism/fatty acid synthase/CYLD引用本文复制引用
陈镇霖,柴鹏,毛洋奇,刘然新,宋烨..ZEB2通过CYLD/FASN轴重编程脂质代谢促进胶质母细胞瘤进展[J].南方医科大学学报,2026,46(6):1290-1300,11.基金项目
国家自然科学基金(82272879) （82272879）
广东省自然科学基金(2023A1515010633) （2023A1515010633）
广州市科技项目(2024B03J0352) Supported by National Natural Science Foundation of China(82272879). （2024B03J0352）
