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Published on: April 1, 2021
[ZEB2 promotes glioblastoma progression by reprogramming lipid metabolism through the CYLD/FASN axis]
Zhenlin Chen1, Peng Chai1, Yangqi Mao1
1Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Objectives:
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.
Conclusions:
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.
