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Page 6 of 18 Yelton et al. Neuroimmunol Neuroinflammation 2018;5:46 I http://dx.doi.org/10.20517/2347-8659.2018.58

particularly glioblastoma, when compared to non-neoplastic tissue. Among the many epigenetic alterations
observed in glioblastomas, changes in HDACs specifically present an opportunity to monitor the
transcriptional status of the genome in these tumors. Preliminary evidence showed that class II and class IV
HDACs display decreases in mRNA expression in glioblastoma when compared to other, more low-grade
[38]
gliomas and normal brain tissues, and an increased amount of acetylation in histone protein H3 . Histone
[39]
modifications are frequent epigenetic changes observed in tumor analysis . Additionally, one large-scale
sequencing study of the protein-coding genes in glioblastomas revealed mutations in two genes HDAC2 and
[40]
HDAC9 . While this handful of preliminary studies have shown that HDAC enzymes see a decrease in
expression, other more recent studies have shown HDAC enzymes seeing an increase in their expression,
further complicating the picture of expression of HDAC enzymes in glioblastomas.

In recent years, further cytologic examinations of tumor samples have revealed an ambiguous picture as to
[41]
the expression of HDAC enzymes in glioblastoma . Looking at studies focusing on the expression patterns
of HDACs in glioblastoma, these tissues seem to exhibit slightly and variably increased HDAC1, HDAC3,
and HDAC6 expression levels as compared to non-neoplastic brain tissues examining both protein and
[42]
mRNA within tissue samples . The findings were further confirmed and even expanded to demonstrate
that HDAC1 and HDAC3 expression levels correlated with WHO tumor grades, with the highest expression
occurring in the most malignant gliomas. HDAC3, in particular, was correlated with poor survival.
[43]
Another study observed that HDAC9 was overexpressed in glioblastomas with a poor prognosis . The
role of SIRT in glioblastoma is currently under debate due to equivocal findings across multiple studies.
While many studies have correlated the down regulation of SIRT1 and SIRT6 in glioblastoma [44,45] , other
studies have shown conflicting evidence as to whether the class II HDAC enzymes act as tumor suppressors
or oncogenes [46,47] . The debate as to the role of class II HDACs will undoubtedly continue as the research
into their roles becomes increasingly robust throughout the years. The classical HDAC family of enzymes
is more clinically relevant as therapeutic agents have been developed to inhibit these aberrant enzymes.
These therapeutic agents are currently undergoing clinical trials and are showing promise as potential new
therapeutic modality for glioblastoma.

Another way to examine the HDAC expression in glioblastoma is to examine the effects and response
displayed by these tumors when treated with HDAC inhibitors. Although this might be a more retrospective
method of analysis and may be less clear due to the ambiguous mechanism of action of many HDAC
inhibitors, this method may give some idea to which HDAC enzymes are aberrantly expressed in these
tumors. We may be able to analyze the HDAC expression in tumor samples but the response of the tumor to
a HDAC inhibitor as a potential therapy is a much more fruitful line of inquiry, emphasizing clinical results
over cytologic curiosities. Ultimately, cytologic examination of glioblastoma tissue indicates which HDAC
enzymes are aberrantly expressed, which goes on to inform which HDAC inhibitor may be useful for that
tumor in particular, offering a potentially personalized approach to glioblastoma treatment. This review
article will reveal that the answers, however, are not always clear-cut and highlight the complicated nature
of these tumors, their protein expression, and their dysregulation leading to increased cell proliferation and
malignant expansion.

HDAC INHIBITORS
While biochemical investigation into HDAC enzyme activities was blossoming in the early 1970s, it
was discovered in 1977 that millimolar concentrations of n-butyrate caused accumulation of acetylated
[48]
[49]
histones . It was subsequently confirmed that n-butyrate acted to inhibit histone deacetylation . However,
a direct causal relationship between these acetylated histones and n-butyrate was non-specific and unable to
be verified, due to the documented effect of n-butyrate on cell membranes and many other enzymes other
than HDAC. Later, the naturally occurring antifungal antibiotic trichostatin A (TSA) was discovered to be
[50]
more potent for HDAC inhibition . TSA, a hydroxamic acid compound, was found to inhibit cell cycle