Glucose Activates SREBPs and Tumor Growth through N-Glycosylation of SCAP

Tumors are commonly characterized by increased lipogenesis and glucose utilization, and elevated glucose consumption is frequently correlated with increased lipogenesis. However, the mechanism connecting tumor glucose metabolism with lipid metabolism remains elusive. Lipogenesis is regulated by a family of transcription factors, the sterol regulatory element-binding proteins (SREBP), which regulate the expression of genes involved in the uptake and synthesis of cholesterol, fatty acids, and phospholipids. When cholesterol concentrations are high, the complex of SREBP and SREBP cleavage-activating protein (SCAP) is blocked in the ER membrane by binding to the ER-anchored protein insulin-induced gene 1 (INSIG1). Cheng and colleagues showed that, in glioblastoma cells, glucose was indispensable for SREBP activation during sterol deprivation. Glucose-mediated activation of SREBPs was accompanied by upregulation of SCAP protein, and SCAP knockdown reduced SREBP activation. N-acetylglucosamine (GlcNAc) was as effective as glucose in increasing SCAP protein levels and activating SREBPs, suggesting that glucose enhances SCAP and activates SREBPs through N-glycosylation of SCAP. Moreover, pharmacologic inhibition of N-glycosylation, but not O-glycosylation, reduced SCAP N-glycosylation and its protein levels, and suppressed SREBP activation, which was rescued by GlcNAc addition. Mechanistically, glucose-driven N-glycosylation of SCAP enhanced its stability by preventing proteasomal degradation. Additionally, glucose-mediated N-glycosylation of SCAP reduced its binding to INSIG1, directing the trafficking of SCAP/SREBP to the Golgi for SREBP activation. Increased glucose uptake driven by EGFR signaling led to the downstream activation of SREBP1 via upregulation of SCAP N-glycosylation. Genetic knockdown of SCAP or mutation of SCAP N-glycosylation sites significantly suppressed EGFRvIII-driven glioblastoma tumor growth. Together, these findings indicate that the N-glycosylation of SCAP is critical for SCAP/SREBP trafficking and SREBP activation. These results reveal an important link between glucose and lipid metabolism in tumors, and suggest that targeting SCAP N-glycosylation may be an effective strategy to disrupt lipid metabolism in cancer.

Cheng C, Ru P, Geng F, Liu J, Yoo JY, Wu X, et al. Glucose-mediated N-glycosylation of SCAP is essential for SREBP-1 activation and tumor growth. Cancer Cell 2015;28:569–81.

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