cell types [21]. As many of the underlying processes of cancer are also important
in inflammation, HDACi may be equally useful in chronic inflammatory diseases
[22, 23]. Importantly, their anti-inflammatory effects generally occur at 10–100-fold
lower concentrations than needed for their cytotoxic effects on cancer cells [24].
The currently FDA-approved HDACi are pan-HDAC inhibitors, which cause an
overall increase in acetylation. Many side effects are expected to originate from this
nonselectivity. To improve HDACi in oncology, it is therefore important to develop
inhibitors that target individual deacetylase isoforms [25]. Isoenzyme selectivity will
be even more crucial in non-oncological applications such as inflammation. For
instance, NF-κB is mostly deacetylated by HDAC3 [26], and selective inhibition of
this deacetylase enables modulation of the NF-κB pathway. Co-inhibiting other
deacetylases might counteract or change these effects. Therefore, the individual
contributions of the various deacetylase isoforms in specific disease models need
to be understood to enable their exploitation as therapeutic targets.
Additionally, apart from their enzymatic activity, HDACs also have roles in the
formation of protein-protein complexes. It is important to be aware of this when
comparing conditional knockout studies to studies using HDAC inhibitors [27]. This
is exemplified by the HDACs 4, 5, 7, and 9 for which their deacetylase activity might
not be crucial for their function [28]. HDAC4, for instance, is unable to efficiently
deacetylate proteins on its own [28]. Instead, this deacetylase binds HDAC3, and the
thus resulting HDAC4/HDAC3 complex has deacetylase activity [27]. Additionally,
these HDACs shuttle between the nucleus and the cytoplasm, and thus their subcellular localization, rather than their expression or activity per se, controls their
actions.
In this chapter we focus on the particular roles of zinc-dependent lysine
deacetylases in models of asthma, COPD, and lung cancer. Additionally, the role
of protein and DNA methylation in these diseases is described.
2 Lysine Deacetylases in Asthma and COPD
2.1 Similarities and Differences Between Asthma and COPD
Asthma and COPD are important examples of chronic inflammatory diseases, which
are characterized by an influx of inflammatory cells in the lungs and an associated
abundance of secreted cytokines. Each disease constitutes a major health burden,
with 328 million people worldwide suffering from moderate to severe COPD and
asthma affecting approximately 300 million [26, 27]. Asthma and COPD both
involve the small airways and cause airflow obstruction and are usually characterized by mucus secretion and bronchoconstriction, leading to breathlessness,
coughing, and eventually severe breathing impairment [29]. The underlying mechanisms of inflammation are, however, different. Asthma is primarily eosinophilic in
nature and driven by CD4+ T cells, while COPD is mostly neutrophilic and
Acetylation and Methylation in Asthma, COPD, and Lung Cancer
433
in inflammation, HDACi may be equally useful in chronic inflammatory diseases
[22, 23]. Importantly, their anti-inflammatory effects generally occur at 10–100-fold
lower concentrations than needed for their cytotoxic effects on cancer cells [24].
The currently FDA-approved HDACi are pan-HDAC inhibitors, which cause an
overall increase in acetylation. Many side effects are expected to originate from this
nonselectivity. To improve HDACi in oncology, it is therefore important to develop
inhibitors that target individual deacetylase isoforms [25]. Isoenzyme selectivity will
be even more crucial in non-oncological applications such as inflammation. For
instance, NF-κB is mostly deacetylated by HDAC3 [26], and selective inhibition of
this deacetylase enables modulation of the NF-κB pathway. Co-inhibiting other
deacetylases might counteract or change these effects. Therefore, the individual
contributions of the various deacetylase isoforms in specific disease models need
to be understood to enable their exploitation as therapeutic targets.
Additionally, apart from their enzymatic activity, HDACs also have roles in the
formation of protein-protein complexes. It is important to be aware of this when
comparing conditional knockout studies to studies using HDAC inhibitors [27]. This
is exemplified by the HDACs 4, 5, 7, and 9 for which their deacetylase activity might
not be crucial for their function [28]. HDAC4, for instance, is unable to efficiently
deacetylate proteins on its own [28]. Instead, this deacetylase binds HDAC3, and the
thus resulting HDAC4/HDAC3 complex has deacetylase activity [27]. Additionally,
these HDACs shuttle between the nucleus and the cytoplasm, and thus their subcellular localization, rather than their expression or activity per se, controls their
actions.
In this chapter we focus on the particular roles of zinc-dependent lysine
deacetylases in models of asthma, COPD, and lung cancer. Additionally, the role
of protein and DNA methylation in these diseases is described.
2 Lysine Deacetylases in Asthma and COPD
2.1 Similarities and Differences Between Asthma and COPD
Asthma and COPD are important examples of chronic inflammatory diseases, which
are characterized by an influx of inflammatory cells in the lungs and an associated
abundance of secreted cytokines. Each disease constitutes a major health burden,
with 328 million people worldwide suffering from moderate to severe COPD and
asthma affecting approximately 300 million [26, 27]. Asthma and COPD both
involve the small airways and cause airflow obstruction and are usually characterized by mucus secretion and bronchoconstriction, leading to breathlessness,
coughing, and eventually severe breathing impairment [29]. The underlying mechanisms of inflammation are, however, different. Asthma is primarily eosinophilic in
nature and driven by CD4+ T cells, while COPD is mostly neutrophilic and
Acetylation and Methylation in Asthma, COPD, and Lung Cancer
433