(p300/CBP) and (3) Moz, Ybf2/Sas3, Sas2, Tip60 (MYST). Other three families
have also been classified as HAT for their similarity: (1) the nuclear receptor
coactivator (NCOA)-related HAT family, (2) transcription factor-related HAT family and (3) the novel Camello HAT family.
The HATs are predominantly expressed in both the nucleus and cytoplasm, while
some of them are also found in cytoplasmatic organelles such as mitochondria and
endoplasmic reticulum [2, 3]. The main function shared by all HAT members is the
activation of transcription. At least three different mechanisms of transcriptional
activation mediated by HATs have been described. In the first, HATs can directly
acetylate their targets (histone proteins and transcriptional factors) to facilitate a
transcriptional response [4]. The histone acetylation facilitates the unwinding of the
chromatin structure, while the acetylation of transcriptional factors can increase their
DNA binding affinity, so leading to an increase in transactivation and gene expression [5, 6]. Alternatively, a HAT enzyme can act as a bridge connecting transcription
factors to the transcription machinery or as a protein scaffold contributing to the
assembly of multi-protein complexes that promote transcriptional activation [7].
Nowadays, it is clear that HAT members do not exclusively control nuclear
transcription or transcriptional factors, but they can also act in other cellular compartments thus regulating cellular processes not directly related to transcriptional
activation [1]. For their multiple biological functions, HATs play a key role in the
pathogenesis of several diseases, including cancer and neurodegenerative disorders.
Although a growing body of evidence demonstrates a direct relationship between
HATs and cancer and suggests them as new therapeutic targets, HAT inhibitors
(HATi) are still in preclinical development [8, 9]. Herein, we summarize the
biological functions of the main HAT members, their role in human disorders and
the most promising inhibitors identified so far.
2 HAT Superfamilies
The four histone subtypes (histone H2A, H2B, H3 and H4) are the main substrates for
the p300/CBP family. The p300/CBP family comprises only two protein members with
interchangeable functions, CBP and its paralog p300. They show similar structures and
share 86% sequence identity at the HAT domains. The HAT domain of p300/CBP
consists of about 500 residues located in the central region of the protein. p300/CBP
contain several other protein domains, including a bromodomain (BRD) and three
cysteine-histidine-rich domains (TAZ, PHD and ZZ) serving for protein-protein interaction. So far, a plethora of interacting proteins, including cofactors and transcription
factors, has been identified thus confirming the relevant role of this family in the
transcriptional control. In this context, p300/CBP act as a bridge connecting transcription factors to the transcription machinery, but also directly acetylate histones and/or
transcription factors to facilitate a transcriptional response [7]. It has been reported
that p300/CBP modulate the activity and cellular localization of different factors
producing multiple downstream effects. For example, the acetylation on Stat3 by
Histone Acetyltransferase Enzymes: From Biological Implications to Most. . .
97
have also been classified as HAT for their similarity: (1) the nuclear receptor
coactivator (NCOA)-related HAT family, (2) transcription factor-related HAT family and (3) the novel Camello HAT family.
The HATs are predominantly expressed in both the nucleus and cytoplasm, while
some of them are also found in cytoplasmatic organelles such as mitochondria and
endoplasmic reticulum [2, 3]. The main function shared by all HAT members is the
activation of transcription. At least three different mechanisms of transcriptional
activation mediated by HATs have been described. In the first, HATs can directly
acetylate their targets (histone proteins and transcriptional factors) to facilitate a
transcriptional response [4]. The histone acetylation facilitates the unwinding of the
chromatin structure, while the acetylation of transcriptional factors can increase their
DNA binding affinity, so leading to an increase in transactivation and gene expression [5, 6]. Alternatively, a HAT enzyme can act as a bridge connecting transcription
factors to the transcription machinery or as a protein scaffold contributing to the
assembly of multi-protein complexes that promote transcriptional activation [7].
Nowadays, it is clear that HAT members do not exclusively control nuclear
transcription or transcriptional factors, but they can also act in other cellular compartments thus regulating cellular processes not directly related to transcriptional
activation [1]. For their multiple biological functions, HATs play a key role in the
pathogenesis of several diseases, including cancer and neurodegenerative disorders.
Although a growing body of evidence demonstrates a direct relationship between
HATs and cancer and suggests them as new therapeutic targets, HAT inhibitors
(HATi) are still in preclinical development [8, 9]. Herein, we summarize the
biological functions of the main HAT members, their role in human disorders and
the most promising inhibitors identified so far.
2 HAT Superfamilies
The four histone subtypes (histone H2A, H2B, H3 and H4) are the main substrates for
the p300/CBP family. The p300/CBP family comprises only two protein members with
interchangeable functions, CBP and its paralog p300. They show similar structures and
share 86% sequence identity at the HAT domains. The HAT domain of p300/CBP
consists of about 500 residues located in the central region of the protein. p300/CBP
contain several other protein domains, including a bromodomain (BRD) and three
cysteine-histidine-rich domains (TAZ, PHD and ZZ) serving for protein-protein interaction. So far, a plethora of interacting proteins, including cofactors and transcription
factors, has been identified thus confirming the relevant role of this family in the
transcriptional control. In this context, p300/CBP act as a bridge connecting transcription factors to the transcription machinery, but also directly acetylate histones and/or
transcription factors to facilitate a transcriptional response [7]. It has been reported
that p300/CBP modulate the activity and cellular localization of different factors
producing multiple downstream effects. For example, the acetylation on Stat3 by
Histone Acetyltransferase Enzymes: From Biological Implications to Most. . .
97