Jeffrey Yunhua Guo

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

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.

Inhibition of SOAT1 suppresses glioblastoma growth via blocking SREBP-1-mediated lipogenesis

Purpose: Elevated lipogenesis regulated by sterol regulatory element-binding protein-1 (SREBP-1), a transcription factor playing a central role in lipid metabolism, is a novel characteristic of glioblastoma (GBM). The aim of this study was to identify effective approaches to suppress GBM growth by inhibition of SREBP-1. As SREBP activation is negatively regulated by endoplasmic reticulum (ER) cholesterol, we sought to determine whether suppression of sterol O-acyltransferase (SOAT), a key enzyme converting ER cholesterol to cholesterol esters (CE) to store in lipid droplets (LDs), effectively suppressed SREBP-1 and blocked GBM growth. Experimental Design: The presence of LDs in glioma patient tumor tissues was analyzed using immunofluorescence, immunohistochemistry, and electronic microscopy. Western blotting and real-time PCR were performed to analyze protein levels and gene expression of GBM cells, respectively. Intracranial GBM xenografts were used to determine the effects of genetically silencing SOAT1 and SREBP-1 on tumor growth. Results: Our study unraveled that cholesterol esterification and LD formation are signature of GBM, and human patients with glioma possess elevated LDs that correlate with GBM progression and poor survival. We revealed that SOAT1 is highly expressed in GBM and functions as a key player in controlling the cholesterol esterification and storage in GBM. Targeting SOAT1 suppresses GBM growth and prolongs survival in xenograft models via inhibition of SREBP-1–regulated lipid synthesis. Conclusions: Cholesterol esterification and storage in LDs are novel characteristics of GBM, and inhibiting SOAT1 to block cholesterol esterification is a promising therapeutic strategy to treat GBM by suppressing SREBP-1. Clin Cancer Res; 22(21); 5337–48. ©2016 AACR.

Abstract 3555: Lipid droplets, a novel metabolic target in glioblastoma

Lipid metabolism reprogramming is a novel feature of malignancies. Identifying the vulnerability of lipid alteration in tumor cells provides a new window to treat cancer. Here, we unraveled that glioblastoma (GBM) patients containing high levels of lipid droplets (LDs), special organelles storing cholesterol esters and triglycerides in cells, presented poor survival. We found that LDs largely formed in tumor tissues from GBM patients, but rarely in low grade of gliomas and normal brain tissues, demonstrating that LDs might serve as a novel diagnostic biomarker and prognostic marker for GBM. We further revealed that sterol O-acyltransferase 1 (SOAT1), the key enzyme controlling cholesterol esterification and LD formation, is highly expressed and correlated with LD prevalence in tumor tissues from GBM patients. Genetic or pharmacologic inhibition SOAT1 using avasimibe, a phase III clinical trial drug in human atherosclerosis patients, significantly suppressed GBM growth and prolongs survival in xenograft models. Moreover, we found that inhibiting SOAT1 suppressed sterol regulatory element-binding protein-1 (SREBP-1), a key transcription factor playing a central role in lipid synthesis, underlying the molecular mechanism of targeting SOAT1-mediated GBM growth suppression. In summary, our data demonstrate that LDs/cholesterol esters uniquely formed in tumor tissues provides an ideal target to specifically inhibit GBM cells whereas sparing normal brain tissues, and reveal that blocking cholesterol storage via targeting SOAT1 represents a promising strategy for GBM treatment. Citation Format: Feng Geng, Jeffrey Guo, Xiang Cheng, Xiaoning Wu, Chunming Cheng, Arnab Chakravarti, Deliang Guo. Lipid droplets, a novel metabolic target in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3555. doi:10.1158/1538-7445.AM2017-3555

Abstract 25: SCAP links glucose to lipids for tumor growth

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.