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


METHODS
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.
Department of Radiation Oncology, James Comprehensive Cancer Center & Arthur G James Cancer Hospital, The Ohio State Medical Center, Columbus, Ohio.
Feng
F
Geng
Department of Radiation Oncology, James Comprehensive Cancer Center & Arthur G James Cancer Hospital, The Ohio State Medical Center, Columbus, Ohio.
Xiang
X
Cheng
Department of Radiation Oncology, James Comprehensive Cancer Center & Arthur G James Cancer Hospital, The Ohio State Medical Center, Columbus, Ohio.
Xiaoning
X
Wu
Department of Neurosurgery, James Comprehensive Cancer Center & Arthur G James Cancer Hospital, The Ohio State Medical Center, Columbus, Ohio.
Ji Young
JY
Yoo
Department of Radiation Oncology, James Comprehensive Cancer Center & Arthur G James Cancer Hospital, The Ohio State Medical Center, Columbus, Ohio.
Chunming
C
Cheng
Department of Radiation Oncology, James Comprehensive Cancer Center & Arthur G James Cancer Hospital, The Ohio State Medical Center, Columbus, Ohio.
Jeffrey Yunhua
JY
Guo
Center for Biostatistics, Department of Biomedical Informatics, James Comprehensive Cancer Center & Arthur G James Cancer Hospital, The Ohio State Medical Center, Columbus, Ohio.
Xiaokui
X
Mo
Department of Radiation Oncology, James Comprehensive Cancer Center & Arthur G James Cancer Hospital, The Ohio State Medical Center, Columbus, Ohio.
Peng
P
Ru
Department of Neurosurgery, James Comprehensive Cancer Center & Arthur G James Cancer Hospital, The Ohio State Medical Center, Columbus, Ohio.
Brian
B
Hurwitz
Department of Neurosurgery at University Alabama at Birmingham, Alabama.
Sung-Hak
SH
Kim
Department of Pathology, James Comprehensive Cancer Center & Arthur G James Cancer Hospital, The Ohio State Medical Center, Columbus, Ohio.
Jose
J
Otero
Department of Neurosurgery, James Comprehensive Cancer Center & Arthur G James Cancer Hospital, The Ohio State Medical Center, Columbus, Ohio.
Vinay
V
Puduvalli
CarMeN Laboratory, INSERM U1060, INRA 1397, Faculté de Médecine Lyon Sud, University de Lyon, Oullins, France.
Etienne
E
Lefai
Department of Surgery, James Comprehensive Cancer Center & Arthur G James Cancer Hospital, The Ohio State Medical Center, Columbus, Ohio.
Jianjie
J
Ma
Department of Neurosurgery at University Alabama at Birmingham, Alabama.
Ichiro
I
Nakano
Departments of Pathology and Neurosurgery at Northwestern University, Chicago, Illinois.
Craig
C
Horbinski
Department of Neurosurgery, James Comprehensive Cancer Center & Arthur G James Cancer Hospital, The Ohio State Medical Center, Columbus, Ohio.
Balveen
B
Kaur
Department of Radiation Oncology, James Comprehensive Cancer Center & Arthur G James Cancer Hospital, The Ohio State Medical Center, Columbus, Ohio.
Arnab
A
Chakravarti
Department of Radiation Oncology, James Comprehensive Cancer Center & Arthur G James Cancer Hospital, The Ohio State Medical Center, Columbus, Ohio. deliang.guo@osumc.edu.
Deliang
D
Guo
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002784:Cholesterol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism*; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D050155:Lipogenesis / Q000187:drug effects*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000037:antagonists & inhibitors*; D055815:Young Adult
D000970:Antineoplastic Agents; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D002784:Cholesterol; D002785:Sterol O-Acyltransferase; C493492:sterol O-acyltransferase 1