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.

Glioblastoma cells induce differential glutamatergic gene expressions in human tumor-associated microglia/macrophages and monocyte-derived macrophages

“…Altogether, these data strengthen the therapeutic potential of xCT targeting strategies that would be beneficial to reduce or switch off glutamate metabolism in glioblastoma cells and keep TAMs in a neuroprotective state needed to restore homeostasis after tumor elimination. 36,37 Collectively, these data suggest a putative neuroprotective role of TAMs by taking up excess extracellular glutamate by increasing expressions of glutamate transporters and glutamine synthetase. This response is not completely mimicked by MDMs exposed to tumor cells, further emphasizing the difference in origin between these bone-marrow derived myeloid cells and the yolk sac-derived microglia.…”

Redox-Mediated Suberoylanilide Hydroxamic Acid Sensitivity in Breast Cancer

“…In this regard, it has been shown that SAHA treatment in glioblastoma cells induces downregulation of xCT, a glutamate-cysteine transporter that controls the intracellular level of reduced glutathione (67). Accordingly, in triple negative breast cancer cells, it has been shown that xCT knockout increases doxorubicin efficacy (60).…”

Opportunities and challenges of radiotherapy for treating cancer

“…Not surprisingly, multiple end points for HDAC-inhibitor activity have been reported, including gene expression, cell-cycle arrest, cell differentiation, antiangiogenesis, cell death, and autophagy. 81 In addition, HDAC inhibitors have been reported to generate ROS and modulate redox levels in cells, [82][83][84][85][86][87] resulting in DNA damage and activation of the DDR. 88,89 Others have shown that key DNA-repair molecules including Ku70/Ku80, DNA-PK, RAD50, RAD51, BRCA1/2, and MRE11 are downregulated by vorinostat and other HDAC inhibitors in combination with radiotherapy, leading to RIF persistence.…”

“…162 Interestingly, the HDAC inhibitor vorinostat has been shown to normalize xCTcontaining transporter levels in gliomas with an accompanying increase in ROS levels. 86 The cysteine transport system maintains intracellular cysteine and glutathione pools in many cells to counter oxidative stress. This system is under control of nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), which provides a potential link for CSC radioresistance through expression of free-radical scavengers.…”