Histone deacetylases inhibition by SAHA/Vorinostat normalizes the glioma microenvironment via xCT equilibration
Wolf I, Fan Z, Rauh M, Seufert S, Hore N, Buchfelder M, Savaskan NE, Eyupoglu IY (2014)
Publication Type: Journal article
Publication year: 2014
Journal
Book Volume: 4
Pages Range: 6226
DOI: 10.1038/srep06226
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 with CRIS profile
Ines Wolf
Medizinische Fakultät
Zheng Fan
Department of Neurosurgery
Manfred Rauh
Department of Paediatrics and Adolescent Medicine
Michael Buchfelder
Lehrstuhl für Neurochirurgie
Involved external institutions
Germany (DE)How to cite
APA:
Wolf, I., Fan, Z., Rauh, M., Seufert, S., Hore, N., Buchfelder, M.,... Eyupoglu, I.Y. (2014). Histone deacetylases inhibition by SAHA/Vorinostat normalizes the glioma microenvironment via xCT equilibration. Scientific Reports, 4, 6226. https://doi.org/10.1038/srep06226
MLA:
Wolf, Ines, et al. "Histone deacetylases inhibition by SAHA/Vorinostat normalizes the glioma microenvironment via xCT equilibration." Scientific Reports 4 (2014): 6226.
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