title: Histone deacetylases inhibition by SAHA/Vorinostat normalizes the glioma microenvironment via xCT equilibration.
abstract: Malignant gliomas are characterized by neurodegenerative actions leading to the destruction of surrounding brain parenchyma. The disturbance in glutamate homeostasis caused by increased expression of the glutamate transporter xCT plays a key role in glioma progression. We demonstrate that the HDAC-inhibitor SAHA specifically inhibits the xCT-transporter expression. Thereby, tumor cell stress is engendered, marked by increase in ROS. Moreover, SAHA dependent xCT-reduction correlates with the inhibition of ATF4-expression, a factor known to foster xCT expression. Since xCT/system Xc- is pivotal for the brain tumor microenvironment, normalization of this system is a key in the management of malignant gliomas. To date, the problem lay in the inability to specifically target xCT due to the ubiquitous expression of the xCT-transporter--i.e. in non-cancerously transformed cells too--as well as its essential role in physiological CNS processes. Here, we show xCT-transporter equilibration through SAHA is specific for malignant brain tumors whereas SAHA does not affect the physiological xCT levels in healthy brain parenchyma. Our data indicate that SAHA operates on gliomas specifically via normalizing xCT expression which in consequence leads to reduced extracellular glutamate levels. This in turn causes a marked reduction in neuronal cell death and normalized tumor microenvironment.
authors.affiliation: 1] Department of Neurosurgery, Universitätsklinikum Erlangen, Friedrich Alexander Universität Erlangen-Nürnberg (FAU) [2].
authors.forename: Ines M L
authors.initials: IM
authors.lastname: Wolf
authors.affiliation: 1] Department of Neurosurgery, Universitätsklinikum Erlangen, Friedrich Alexander Universität Erlangen-Nürnberg (FAU) [2].
authors.forename: Zheng
authors.initials: Z
authors.lastname: Fan
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University of Erlangen-Nuremberg.
authors.forename: Manfred
authors.initials: M
authors.lastname: Rauh
authors.affiliation: Institute of Human Genetics, University of Cologne.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Seufert
authors.affiliation: Department of Neurosurgery, Universitätsklinikum Erlangen, Friedrich Alexander Universität Erlangen-Nürnberg (FAU).
authors.forename: Nirjhar
authors.initials: N
authors.lastname: Hore
authors.affiliation: Department of Neurosurgery, Universitätsklinikum Erlangen, Friedrich Alexander Universität Erlangen-Nürnberg (FAU).
authors.forename: Michael
authors.initials: M
authors.lastname: Buchfelder
authors.affiliation: 1] Department of Neurosurgery, Universitätsklinikum Erlangen, Friedrich Alexander Universität Erlangen-Nürnberg (FAU) [2].
authors.forename: Nic E
authors.initials: NE
authors.lastname: Savaskan
authors.affiliation: 1] Department of Neurosurgery, Universitätsklinikum Erlangen, Friedrich Alexander Universität Erlangen-Nürnberg (FAU) [2].
authors.forename: Ilker Y
authors.initials: IY
authors.lastname: Eyüpoglu
mesh_terms: D027182:Amino Acid Transport System y+ / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects*; D000077337:Vorinostat
chemical_list: D027182:Amino Acid Transport System y+; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C118895:SLC7A11 protein, human; D000077337:Vorinostat; D006655:Histone Deacetylases