Abstract 25: SCAP links glucose to lipids for tumor growth

Abstract Increased glucose consumption and elevated lipogenesis are co-occurred in malignancies. But the molecular mechanism of the link between glucose and lipid metabolism remains elusive. Our previous studies have uncovered that sterol regulatory element-binding protein (SREBP-1), an endoplasmic reticulum-bound transcription factor with a central role in lipid metabolism, is highly upregulated in glioblastoma (GBM), the most deadly brain tumor. In the current study, we found that SREBP-cleavage activating protein (SCAP), a key player regulating SREBP trafficking from ER to the Golgi and subsequent SREBP activation, links oncogenic signaling and glucose consumption to lipid metabolism. Our data showed that glucose is a critical activator for SREBP function via N-glycosylation of SCAP. N-glycosylation is a key signal to promote SCAP/SREBP complex move from ER to the Golgi and SREBP activation. Moreover, we found that EGFR/PI3K/Akt signaling activates SREBP-1 via upregulation of SCAP N-glycosylation and its protein levels through enhancing glucose uptake. Genetically silencing SCAP or mutation of the N-glycosylation sites on SCAP downregulates SREBP-1 activity and impairs GBM tumor growth. Taken together, our study revealed that glucose is a critical activator for SREBP-1 function and lipid metabolism, and SCAP integrates oncogenic signaling and fuel availability to SREBP-1-mediated lipogenesis for tumor growth. Our study also demonstrated that targeting SCAP N-glycosylation represents a promising therapeutic strategy to treat malignancies. Citation Format: Chunming Cheng, Feng Geng, Jeffrey Yunhua Guo, Xiaoning Wu, Xiang Cheng, Arnab Chakravarti, Deliang Guo. SCAP links glucose to lipids for tumor growth. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 25.