Glucose-Mediated N-glycosylation of SCAP Is Essential for SREBP-1 Activation and Tumor Growth
Résumé
Tumorigenesis is associated with increased glucose consumption and lipogenesis, but how these pathways are interlinked is unclear. Here, we delineate a pathway in which EGFR signaling, by increasing glucose uptake, promotes N-glycosylation of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) and consequent activation of SREBP-1, an ER-bound transcription factor with central roles in lipid metabolism. Glycosylation stabilizes SCAP and reduces its association with Insig-1, allowing movement of SCAP/SREBP to the Golgi and consequent proteolytic activation of SREBP. Xenograft studies reveal that blocking SCAP N-glycosylation ameliorates EGFRvIII-driven glioblastoma growth. Thus, SCAP acts as key glucose-responsive protein linking oncogenic signaling and fuel availability to SREBP-dependent lipogenesis. Targeting SCAP N-glycosylation may provide a promising means of treating malignancies and metabolic diseases.
Mots clés
Neoplasms/genetics/*metabolism/pathology
Confocal
Microscopy
Nude
Mice
Membrane Proteins/genetics/*metabolism
MCF-7 Cells
Intracellular Signaling Peptides and Proteins/genetics/*metabolism
Hep G2 Cells
Golgi Apparatus/metabolism
Glycosylation/drug effects
Survival Analysis
Sterol Regulatory Element Binding Protein 1/genetics/*metabolism
Glucose/metabolism/pharmacology
RNA Interference
HEK293 Cells
Cell Line
Western
Blotting
Protein Binding
Animals
Humans
Female
Transplantation
Heterologous
Tumor Burden/genetics