that were initially discovered to act on histones [7]. Therefore, the actions on
nonhistone proteins need always be taken into account when evaluating the effects
of epidrugs.
1.3 Protein Lysine Acetylation and Deacetylation
Besides histones, principally any protein with a lysine can undergo a dynamic
process of acetylation and deacetylation at some point during its lifetime [8]. One
study mapped over 3,600 of such acetylation sites on approximately 1,750 proteins
[9]. This so-called acetylome is under the control of acetyltransferases and
deacetylases, of which many isoforms exist. To date, 18 deacetylases are known,
which are grouped into two families based on their dependency on either zinc or
nicotinamide adenine dinucleotide as cofactor [10]. Members of the latter family are
called sirtuins. Deacetylases that contain zinc are still mostly called histone
deacetylases (HDACs), named after their firstly discovered target, and are further
divided into four different classes based on sequence similarity. The functionally
opposing group of proteins that show acetyltransferase activity is even larger and
more diverse [11].
1.4 Relevance of Deacetylases in Disease and Their Potential
as Drug Targets
Protein acetylation influences important protein properties. Next to altering
DNA-protein interactions, protein-protein interactions, subcellular localization, and
even transcriptional activity can all be tuned by the dynamic process of acetylation
[12–14]. Acetylation of the transcription factor p53, for example, destabilizes the
interaction with its negative regulator Mdm2, thereby activating p53 and ultimately
leading to an increase in the expression of apoptosis and growth arrest-inducing
genes [15]. In a similar fashion, acetylation of the p65 subunit of nuclear factorkappa B (NF-κB), an important inflammatory transcription factor [16], influences its
subcellular location and transcriptional activity [17]. Since acetylation is a posttranslational modification with fundamental importance for the function of key proteins, it
is not surprising that acetylation patterns are distorted in various diseases. In cancer,
p53 is acetylated to a lesser extent, allowing cells to grow rapidly [18]. In ulcerative
colitis and other inflammatory diseases, the acetylation status of NF-κB is changed,
resulting in an increased expression of cytokines [18, 19]. Consequently, small
molecule inhibitors of HDACs (HDACi), which increase acetylation by repressing
deacetylation, are in over 100 clinical trials for cancer and may also enter clinical
trials for inflammatory diseases [20]. So far, four HDACi have been FDA-approved,
and these are known to relatively selectively induce apoptosis in a number of tumor
432
M. R. H. Zwinderman et al.
nonhistone proteins need always be taken into account when evaluating the effects
of epidrugs.
1.3 Protein Lysine Acetylation and Deacetylation
Besides histones, principally any protein with a lysine can undergo a dynamic
process of acetylation and deacetylation at some point during its lifetime [8]. One
study mapped over 3,600 of such acetylation sites on approximately 1,750 proteins
[9]. This so-called acetylome is under the control of acetyltransferases and
deacetylases, of which many isoforms exist. To date, 18 deacetylases are known,
which are grouped into two families based on their dependency on either zinc or
nicotinamide adenine dinucleotide as cofactor [10]. Members of the latter family are
called sirtuins. Deacetylases that contain zinc are still mostly called histone
deacetylases (HDACs), named after their firstly discovered target, and are further
divided into four different classes based on sequence similarity. The functionally
opposing group of proteins that show acetyltransferase activity is even larger and
more diverse [11].
1.4 Relevance of Deacetylases in Disease and Their Potential
as Drug Targets
Protein acetylation influences important protein properties. Next to altering
DNA-protein interactions, protein-protein interactions, subcellular localization, and
even transcriptional activity can all be tuned by the dynamic process of acetylation
[12–14]. Acetylation of the transcription factor p53, for example, destabilizes the
interaction with its negative regulator Mdm2, thereby activating p53 and ultimately
leading to an increase in the expression of apoptosis and growth arrest-inducing
genes [15]. In a similar fashion, acetylation of the p65 subunit of nuclear factorkappa B (NF-κB), an important inflammatory transcription factor [16], influences its
subcellular location and transcriptional activity [17]. Since acetylation is a posttranslational modification with fundamental importance for the function of key proteins, it
is not surprising that acetylation patterns are distorted in various diseases. In cancer,
p53 is acetylated to a lesser extent, allowing cells to grow rapidly [18]. In ulcerative
colitis and other inflammatory diseases, the acetylation status of NF-κB is changed,
resulting in an increased expression of cytokines [18, 19]. Consequently, small
molecule inhibitors of HDACs (HDACi), which increase acetylation by repressing
deacetylation, are in over 100 clinical trials for cancer and may also enter clinical
trials for inflammatory diseases [20]. So far, four HDACi have been FDA-approved,
and these are known to relatively selectively induce apoptosis in a number of tumor
432
M. R. H. Zwinderman et al.