Inhibition of SOAT1 Suppresses Glioblastoma Growth via Blocking SREBP-1–Mediated Lipogenesis

Abstract

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 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.

Feedback Loop Regulation of SCAP/SREBP-1 by miR-29 Modulates EGFR Signaling-Driven Glioblastoma Growth

“…Our previous studies have revealed that GBM growth is highly dependent on SCAP/SREBP-1 signaling (Cheng et al, 2015; Geng et al, 2016; Guo et al, 2009b; Guo et al, 2011). We asked whether miR-29 transfection was able to inhibit GBM cell growth through suppressing SCAP/SREBP-1-regulated lipogenesis.…”

“…Recent evidence shows that lipid metabolism is also reprogrammed in malignancies to support rapid tumor growth (Bell and Guo, 2012; Geng et al, 2016; Guo et al, 2013; Guo et al, 2014; Menendez and Lupu, 2007; Ru et al, 2013). In particular, our recent work has revealed that oncogenic EGFR signaling activates lipid metabolism via upregulation of SCAP/SREBP-1 signaling (Cheng et al, 2015; Guo, 2016; Guo et al, 2009b; Guo et al, 2011).…”

SCAP/SREBPs are Central Players in Lipid Metabolism and Novel Metabolic Targets in Cancer Therapy

“…Accumulating evidence has shown that SCAP/SREBPs play important roles in malignancies, connecting oncogenic signaling to lipid metabolism alterations, leading to rapid tumor growth (Figure 1) [13, 60, 61, 76–78, 80, 82]. Multiple studies have suggested that SCAP/SREBPs are very promising molecular targets in cancer treatment.…”

Functional characterization of AMP-activated protein kinase signaling in tumorigenesis

“…Moreover, the correlations between SREBP-1c and neural oncogenesis have also been extensively investigated, in which aberrantly increased expression of SREBP-1c is found inside glioblastoma tissues, which positively relates to tumor growth and local spread by stimulating its downstream targets of ACC and FASN [134]. Additionally, upregulation of SOAT1 [135] and N-glycosylation of SCAP jointly contribute to SREBP-1c activation [136], while miR-132 suppressively targets SREBP-1c and diminishes its oncogenic properties in glioma cells [137]. In summary, based on current literatures, SREBP-1c targeted therapy has a bright future among cancer patients, especially for those with lipid-induced malignancies.…”