Inhibition of SOAT1 suppresses glioblastoma growth via blocking SREBP-1-mediated lipogenesis
2016
Geng, Feng | Cheng, Xiang | Wu, Xiaoning | Yoo, Ji Young | Cheng, Chunming | Guo, Jeffrey Yunhua | Mo, Xiaokui | Ru, Peng | Hurwitz, Brian | Kim, Sung-Hak | Otero, Jose | Puduvalli, Vinay | Lefai, Etienne | Ma, Jianjie | Nakano, Ichiro | Horbinski, Craig | Kaur, Balveen | Chakravarti, Arnab | Guo, Deliang | Department of Radiation Oncology ; St James's Hospital | The Ohio State University [Columbus] (OSU) | Department Neurosurgery ; St James's Hospital | Department of Biomedical Informatics, Center for Biostatistics ; St James's Hospital | Department Neurosurgery ; University of Alabama at Birmingham [ Birmingham] (UAB) | Department Pathology ; St James's Hospital | Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN) ; Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon) ; Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM) | Department Surgery ; St James's Hospital | Department Pathology ; University Vienna | Department Neurosurgery ; Northwestern University [Evanston] | Department Radiation Oncology ; St James's Hospital | NIH/NINDS NS072838 NS079701;American Cancer Society Research Scholar Grant RSG-14-228-01-CSM K08 CA155764;OSUCCC start-up funds;OSU Neuroscience Core MRI pilot grant
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.
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