substrates are modified histones involved in DNA packing by the formation of
nucleosome supramolecular assemblies [6–9]. In addition, HDAC1–HDAC3 are
known to interact with nuclear proteins and to be recruited to multiprotein complexes involved in chromatin remodeling, cell cycle progression, as well as DNA
replication and transcription. HDAC1 and HDAC2 are associated with several
monomeric and homo- and heteropolymeric complexes, such as CoREST
(co-repressor of RE1-silencing transcription factor), MiDAC (mitotic deacetylase
complex), NuRD (nucleosome remodeling and deacetylase), and SIN3
(switch-independent 3); and HDAC3 is recruited to the SMRT/NCoR (nuclear receptor co-repressor 2) complex. These protein partners appear to be essential for the
deacetylase enzymatic activity, as well as for directing HDAC function through
substrate recognition [8]. HDAC8 is also part of the class I, but it is not involved in
such protein complexes and thus thought to prefer biological targets other than histones
[10]. Furthermore, HDAC8 is not able to cleave ε-N-crotonyllysine (Kcr) PTMs as the
other three class I human HDACs, which reflects its functional distinction from
HDAC1–HDAC3 [11, 12].
Similar to class I HDACs, members of class IIa are also localized in the nucleus,
and they have been found to interact with some of the aforementioned protein
partners involved in epigenetic regulation. However, their biological mechanism is
still under discussion, since they lack a key tyrosine residue in the active site, which
appears important for the deacetylase activity and is characteristic of class I HDACs
[13]. Recombinant class IIa HDACs show very poor deacetylase activity in vitro,
whereas they do cleave other non-biologically relevant substrates
[13, 14]. HDAC11, the sole human enzyme member of class IV HDACs, was also
controversial due to poor in vitro deacetylase activity. Interestingly, recent studies
indicate that this isotype is responsible for the removal of ε-N-myristoyllysine
(Kmyr) PTMs [15–17], which was an activity only associated with the sirtuins
previously. Finally, HDAC6 and HDAC10, members of class IIb, are mainly present
in the cytosol and therefore do not directly target chromatin. HDAC6 acts on
α-tubulin among other acetylated proteins in human cells, whereas HDAC10 has
recently been proposed to be a polyamine deacetylase [6, 18].
Initially, scientific interest in HDACs was raised by the observation that some
compounds that induce differentiation and inhibit proliferation of cancer cells also
resulted in the accumulation of hyperacetylated histones. This was the case for
n-butyrate [19], for dimethyl sulfoxide (DMSO) [20], and for the natural products
trichostatin A (TSA, Fig. 1 compound 1.1) [21] and trapoxin A (TpxA) [22]. Parallel
to these findings, Ronald Breslow, Paul A. Marks, and coworkers developed a potent
inducer of murine erythroleukemia cell differentiation, suberoylanilide hydroxamic
acid (SAHA, Fig. 1 compound 1.2) [23]. All these compounds were discovered to
inhibit the deacetylation of histones by targeting HDACs, and SAHA became a
powerful probe for the study of their function, as well as the first of a handful of
HDAC inhibitors approved for cancer treatment [23]. Moreover, targeting HDACs
has not only found relevance against several types of cancer but also against
neurodegenerative and inflammatory diseases [9, 24].
Hydroxamic Acid-Containing Peptides in the Study of Histone Deacetylases
31
nucleosome supramolecular assemblies [6–9]. In addition, HDAC1–HDAC3 are
known to interact with nuclear proteins and to be recruited to multiprotein complexes involved in chromatin remodeling, cell cycle progression, as well as DNA
replication and transcription. HDAC1 and HDAC2 are associated with several
monomeric and homo- and heteropolymeric complexes, such as CoREST
(co-repressor of RE1-silencing transcription factor), MiDAC (mitotic deacetylase
complex), NuRD (nucleosome remodeling and deacetylase), and SIN3
(switch-independent 3); and HDAC3 is recruited to the SMRT/NCoR (nuclear receptor co-repressor 2) complex. These protein partners appear to be essential for the
deacetylase enzymatic activity, as well as for directing HDAC function through
substrate recognition [8]. HDAC8 is also part of the class I, but it is not involved in
such protein complexes and thus thought to prefer biological targets other than histones
[10]. Furthermore, HDAC8 is not able to cleave ε-N-crotonyllysine (Kcr) PTMs as the
other three class I human HDACs, which reflects its functional distinction from
HDAC1–HDAC3 [11, 12].
Similar to class I HDACs, members of class IIa are also localized in the nucleus,
and they have been found to interact with some of the aforementioned protein
partners involved in epigenetic regulation. However, their biological mechanism is
still under discussion, since they lack a key tyrosine residue in the active site, which
appears important for the deacetylase activity and is characteristic of class I HDACs
[13]. Recombinant class IIa HDACs show very poor deacetylase activity in vitro,
whereas they do cleave other non-biologically relevant substrates
[13, 14]. HDAC11, the sole human enzyme member of class IV HDACs, was also
controversial due to poor in vitro deacetylase activity. Interestingly, recent studies
indicate that this isotype is responsible for the removal of ε-N-myristoyllysine
(Kmyr) PTMs [15–17], which was an activity only associated with the sirtuins
previously. Finally, HDAC6 and HDAC10, members of class IIb, are mainly present
in the cytosol and therefore do not directly target chromatin. HDAC6 acts on
α-tubulin among other acetylated proteins in human cells, whereas HDAC10 has
recently been proposed to be a polyamine deacetylase [6, 18].
Initially, scientific interest in HDACs was raised by the observation that some
compounds that induce differentiation and inhibit proliferation of cancer cells also
resulted in the accumulation of hyperacetylated histones. This was the case for
n-butyrate [19], for dimethyl sulfoxide (DMSO) [20], and for the natural products
trichostatin A (TSA, Fig. 1 compound 1.1) [21] and trapoxin A (TpxA) [22]. Parallel
to these findings, Ronald Breslow, Paul A. Marks, and coworkers developed a potent
inducer of murine erythroleukemia cell differentiation, suberoylanilide hydroxamic
acid (SAHA, Fig. 1 compound 1.2) [23]. All these compounds were discovered to
inhibit the deacetylation of histones by targeting HDACs, and SAHA became a
powerful probe for the study of their function, as well as the first of a handful of
HDAC inhibitors approved for cancer treatment [23]. Moreover, targeting HDACs
has not only found relevance against several types of cancer but also against
neurodegenerative and inflammatory diseases [9, 24].
Hydroxamic Acid-Containing Peptides in the Study of Histone Deacetylases
31