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Figure 1. Histone acetyltransferase (HAT) and histone deacetylase (HDAC) in balance - physiologic vs. pathologic. In physiologic
state, HAT enzymes and HDAC enzymes work in tandem to regulate gene transcription. HATs induce an open chromatin conformation
(favoring gene transcription), which is counterbalanced by the action of HDACs that induce a closed chromatin conformation (favoring
gene silencing). In pathologic state (e.g., neoplastic change) this balanced is tipped, favoring either an unregulated open chromatin
conformation or an unregulated closed chromatin conformation. Schematically shown is an instance of an unregulated closed chromatin
conformation due to a pathologic increase in HDAC enzymes. This unregulated, pathologic state may silence physiologic regulatory
pathways in the cell, such as those protein products that regulate the cell cycle genes (e.g., tumor suppressor genes)

Alternatively, HDACs can also be overexpressed in abnormal tissue, leading to the silencing of regulatory
genes [Figure 1]. Over the years, abnormal HDAC transcripts have been linked to multiple pathologies
including neurological diseases, immune disorders, and a multitude of cancers [32,33] .

Cancer is a particular field where HDAC enzymes are heavily implicated, as there are correlations between
[34]
somatic DNA mutations in histone-modifying enzymes and human malignancy . One of the first examples
of note was the discovery of a mutation in HDAC2, leading to microsatellite instability in those individuals
[35]
with hereditary non-polyposis colorectal carcinomas . The expression of HDAC transcripts has also been
found to be variable in tumors when compared to normal somatic tissue, such that newer studies can link
[36]
abnormal HDAC activity in 21 liquid and solid human tumors . These changes in HDAC activity may lead
to changes in histone acetylation status, thereby leading to increase in transcription of human oncogenes or
suppression of tumor suppressor genes. Aberrant expression of HDACs has been shown to be correlated with
[37]
a poor clinical prognosis . These enzymes ultimately play an essential role in the body, providing a stabilizing
force to the action of HATs and effecting epigenetic change. When researchers knew that these enzymes
were often aberrantly expressed in tumors, they began setting their sights on understanding their roles in the
pathogenesis behind one of the deadliest human cancers, glioblastoma.

GLIOBLASTOMA AND DEREGULATION OF HDAC ENZYMES
HDAC enzymes may play a role in the tumorigenesis of glioblastoma through a yet-undetermined
mechanism. HDACs are believed to be effectors of epigenetic changes observed in neoplastic tissue,