Glucose-Mediated N-glycosylation of SCAP Is Essential for SREBP-1 Activation and Tumor Growth

Chunming Cheng; Peng Ru; Feng Geng; Junfeng Liu; Ji Young Yoo; Xiaoning Wu; Xiang Cheng; Vanessa Euthine; Peng Hu; Jeffrey Yunhua Guo; Etienne Lefai; Balveen Kaur; Axel Nohturfft; Jianjie Ma; Arnab Chakravarti; Deliang Guo

doi:10.1016/j.ccell.2015.09.021

Glucose-Mediated N-glycosylation of SCAP Is Essential for SREBP-1 Activation and Tumor Growth

Chunming Cheng, Peng Ru, Feng Geng, Junfeng Liu, Ji Young Yoo, Xiaoning Wu, Xiang Cheng, Vanessa Euthine, Peng Hu, Jeffrey Yunhua Guo, Etienne Lefai, Balveen Kaur, Axel Nohturfft, Jianjie Ma, Arnab Chakravarti, Deliang Guo

Research output: Contribution to journal › Article › peer-review

182 Scopus citations

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.

Original language	English (US)
Pages (from-to)	569-581
Number of pages	13
Journal	Cancer Cell
Volume	28
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2015.09.021
State	Published - Nov 9 2015
Externally published	Yes

Keywords

EGFR signaling
Glioblastoma
Insig-1
N-glycosylation
SCAP
SREBP-1

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2015.09.021

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@article{24a95a57b99d40a19fa9ad84005211ea,

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.",

keywords = "EGFR signaling, Glioblastoma, Insig-1, N-glycosylation, SCAP, SREBP-1",

author = "Chunming Cheng and Peng Ru and Feng Geng and Junfeng Liu and Yoo, {Ji Young} and Xiaoning Wu and Xiang Cheng and Vanessa Euthine and Peng Hu and Guo, {Jeffrey Yunhua} and Etienne Lefai and Balveen Kaur and Axel Nohturfft and Jianjie Ma and Arnab Chakravarti and Deliang Guo",

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year = "2015",

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doi = "10.1016/j.ccell.2015.09.021",

language = "English (US)",

volume = "28",

pages = "569--581",

journal = "Cancer Cell",

issn = "1535-6108",

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TY - JOUR

T1 - Glucose-Mediated N-glycosylation of SCAP Is Essential for SREBP-1 Activation and Tumor Growth

AU - Cheng, Chunming

AU - Ru, Peng

AU - Geng, Feng

AU - Liu, Junfeng

AU - Yoo, Ji Young

AU - Wu, Xiaoning

AU - Cheng, Xiang

AU - Euthine, Vanessa

AU - Hu, Peng

AU - Guo, Jeffrey Yunhua

AU - Lefai, Etienne

AU - Kaur, Balveen

AU - Nohturfft, Axel

AU - Ma, Jianjie

AU - Chakravarti, Arnab

AU - Guo, Deliang

PY - 2015/11/9

Y1 - 2015/11/9

N2 - 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.

AB - 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.

KW - EGFR signaling

KW - Glioblastoma

KW - Insig-1

KW - N-glycosylation

KW - SCAP

KW - SREBP-1

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JO - Cancer Cell

JF - Cancer Cell

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ER -

Glucose-Mediated N-glycosylation of SCAP Is Essential for SREBP-1 Activation and Tumor Growth

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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