title: Glucose-Mediated N-glycosylation of SCAP Is Essential for SREBP-1 Activation and Tumor Growth.
abstract: 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.
authors.affiliation: Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Chunming
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Ru
authors.affiliation: Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Geng
authors.affiliation: Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA; College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, PR China.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Yoo
authors.affiliation: Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Cheng
authors.affiliation: CarMeN Laboratory, INSERM U1060, INRA 1397, Faculté de Médecine Lyon Sud BP 12, Université de Lyon, 69921 Oullins Cedex, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Euthine
authors.affiliation: Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Hu
authors.affiliation: Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Jeffrey Yunhua
authors.initials: JY
authors.lastname: Guo
authors.affiliation: CarMeN Laboratory, INSERM U1060, INRA 1397, Faculté de Médecine Lyon Sud BP 12, Université de Lyon, 69921 Oullins Cedex, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Lefai
authors.affiliation: Department of Neurosurgery, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
authors.affiliation: Vascular Biology Research Centre, St. George's University of London, London SW17 0RE, UK.
authors.forename: Axel
authors.initials: A
authors.lastname: Nohturfft
authors.affiliation: Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Medical Center, Columbus, OH 43210, USA.
authors.forename: Jianjie
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Arnab
authors.initials: A
authors.lastname: Chakravarti
authors.affiliation: Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA. Electronic address: deliang.guo@osumc.edu.
authors.forename: Deliang
authors.initials: D
authors.lastname: Guo
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D005260:Female; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006031:Glycosylation / Q000187:drug effects; D006056:Golgi Apparatus / Q000378:metabolism; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D034622:RNA Interference; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics
chemical_list: C108626:INSIG1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497387:SREBF1 protein, human; C102196:SREBP cleavage-activating protein; D051780:Sterol Regulatory Element Binding Protein 1; D005947:Glucose
keywords: EGFR signaling; Insig-1; N-glycosylation; SCAP; SREBP-1; glioblastoma