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signals from the blood, regulating entry and exit of molecules from the blood and the CNS, and even
[15]
changing as the somatic demands of the barrier changes . This physiological barrier is often deregulated
due to development of a brain malignancy such as glioblastoma, which again endorses the notion that
[16]
tumors within the brain are inaccessible to the therapeutic agents as they cannot cross the BBB . This
fundamental change in understanding of how the BBB functions along with the rise of immunotherapy
as a promising cancer treatment modality has opened wide the application of this therapy as a potential
[17]
treatment for GBM , which in the past has been extremely difficult to treat.
One specific modality of immunotherapy that has shown some promise in the treatment of GBM is the
use of epigenetic modulators. Histone deacetylases (HDACs) play important roles in epigenetic changes
and HDAC inhibitors as immunomodulatory agents have been useful in the preclinical arena to promote
immune-mediated destruction of neoplastic cells in the CNS. These epigenetic modulators work to alter
gene expression without alteration of the DNA sequences, through modulation of specific signaling
[18]
cascades within the tumor . In fact, one specific class of compounds that have currently shown promise
[19]
in epigenetic modulation of GBM cells are the HDAC inhibitors . This epigenetic approach towards
cancer therapy involves tipping the balance between the activity of two different enzyme families, histone
acetyltransferases (HATs) and HDACs. HATs have classically been involved in increasing gene expression,
while HDACs have been associated with gene silencing. Mutations in HDAC enzymes have been linked to
tumor development, due to the lack of inactivation of aberrant genes involved in the regulation of important
[20]
cellular functions including cell proliferation, cell cycle regulation, and apoptosis . Following the discovery
of these dysregulated pathways in tumor cells, investigation into HDAC inhibitors has become an active area
of research. Some of these agents had questionable efficacy when used as monotherapy against many human
tumors, but when utilized in combination therapies with standard-of-care treatment regimens, they showed
[21]
synergistic or additive effects . In glioblastoma specifically, this treatment modality has demonstrated
[22]
both induction of apoptosis and promotion of antitumor immunity providing a potential method of
immunotherapy directed against glioblastoma.

In this review article, we seek to examine the current understanding of HDAC enzymes, describe progress
in the development of HDAC inhibitors being used to treat glioblastoma, and report other potential
immunomodulatory agents and immunotherapy modalities with a potential to be directed to glioblastoma.
As unvaryingly lethal as this tumor is, the potential of novel therapeutic agents must not be overlooked in
HDAC inhibitors because any new therapy may provide a new chance at remission for glioblastoma patients
who are in desperate need of novel approaches towards fighting their malignant condition.

HDAC ENZYMES
HDAC enzymes serve as some of the most important effectors of epigenetic changes in the human body.
[23]
First isolated from a calf thymus extract , HDACs were found to catalyze the removal of acetyl groups from
lysine residues of both histone and non-histone proteins, thereby effecting transcriptional changes within the
[24]
cells . This function of histone deacetylation was suspected to be caused by a complex of multiple enzymes,
but early chromatography studies were unable to differentiate the function of individual enzymes that made
up this complex. However, this state of understanding changed significantly following the cloning of the
[25]
first HDAC enzyme in 1996 (aptly described as HDAC1 in the literature) . This began a wave of research
publications fully describing these enzymes and their functions. Today, there are 18 different human HDAC
enzymes divided into two separate families and four classes based on their similarities to their yeast enzyme
counterparts [Table 1].

All 18 HDAC enzymes belong to either the HDAC family or the silent information regulator 2 (Sir2) family,
with the human versions of these enzymes being further subcategorized into the classes based on their
similarities in amino acid sequence. HDAC1, HDAC2, HDAC3, and HDAC8 are all class I proteins with