Histone deacetylase 6 (HDAC6), by deacetylation of multiple substrates and association with interacting proteins, regulates many physiological processes that are involved in cancer development and invasiveness such as cell proliferation, apoptosis, motility, epithelial to mesenchymal transition, and angiogenesis. Due to its ability to remove misfolded proteins, induce autophagy, and regulate unfolded protein response, HDAC6 plays a protective role in responses to stress and enables tumor cell survival.
1. Introduction
HDAC6 has gained a lot of attention since its discovery in 1999
[1]. It consists of 1215 amino acids and possesses five functional domains (
Figure 1). Starting from its N- to the C- terminus, HDAC6 comprises the following regions: a nuclear localization sequence (NLS) that is rich in arginine (Arg) and Lys, a nuclear export sequence (NES) that is rich in leucine (Leu), two catalytic deacetylase domains (CD1 and CD2), the cytoplasmic anchoring serin (Ser) glutamine (Glu)-containing tetrapeptide (SE14), and a ubiquitin-binding zinc finger motif domain (ZnF-UBP). NLS and NES together control the trafficking of HDAC6 between the nucleus and the cytoplasm, while SE14 is responsible for the intracellular retention of HDAC6. HDAC6 also contains a dynein motor-binding sequence (DMBS) between the CD1 and CD2 catalytic domains
[1][2][3][4].
Figure 1. Functional domains of histone deacetylase (HDAC) 6: NLS—nuclear localization sequence, NES—nuclear export sequence; two catalytic domains (CD1 and CD2), DMBS—dynein motor-binding sequence, ZnF-UBP—zinc finger ubiquitin-binding domain, U—ubiquitin. Acetylation of NLS by p300 inhibits HDAC6 interaction with importin-α. Ras/Raf/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK), epidermal growth factor receptor (EGFR), G protein-coupled receptor kinase (GRK) 2, casein kinase (CK) 2, and glycogen synthase kinase (GSK) 3β signaling phosphorylate and activate HDAC6.
With the two catalytic domains, HDAC6 is a unique class IIb HDAC, responsible for the deacetylation of a number of non-histone substrates involved in the regulation of crucial physiological processes, including cell proliferation, survival, apoptosis, autophagy, motility, intracellular transport, and stress responses. HDAC6 regulates the deacetylation of multiple cytoplasmic substrates and affects their activity, cellular location, and protein–protein interactions. The deacetylase activity of both catalytic domains is Zn
2+ dependent. The CD1 catalytic domain mostly deacetylates C-terminal acetyl-Lys residues and cannot independently exert catalytic activity but needs CD2 assistance. Aside from its deacetylase activity, HDAC6, through the catalytic CD1 domain, exhibits E3 ubiquitin ligase activity
[3]. Proteins in the cytoplasm that are identified as substrates for deacetylation by HDAC6 include α-tubulin, cortactin, heat shock protein (Hsp) 90, heat shock transcription factor-1 (HSF-1), Ku70, p53, peroxiredoxins, signal transducer and activator of transcription (STAT) 3, forkhead box protein O1 (FOXO1), and β-Catenin
[2][5][6][7][8] (
Table 1).
Table 1. HDAC6 substrates and physiological functions of HDAC6-mediated deacetylation.
Protein |
Localization |
Function |
Reference |
α-tubulin |
Cytoplasm |
Microtubule disassembly, increases cell motility |
[9][10][11][12] |
Cortactin |
Cytoplasm |
Actin polymerization and branching, increases cell motility |
[13] |
TFEB |
Cytoplasm |
Autophagy |
[14] |
FOXO1 |
Cytoplasm |
Autophagy |
[15] |
Hsp90 |
Cytoplasm |
Degradation of misfolded proteins |
[16] |
GRP78 |
Cytoplasm and nucleus |
ER stress regulation, tumor progression via secretion of exosomes |
[17] |
NF-κB |
Nucleus |
Transcription of genes for NLRP3, pro-IL-1β, pro-IL-18, inflammasome activity |
[18] |
P53 |
Cytoplasm |
Cell cycle progression, inhibition of apoptosis, induced autophagy via upregulation of Beclin-1 |
[19][20][21] |
Ku70 |
Cytoplasm |
Suppression of apoptosis |
[8][22] |
Survivin |
Nucleus |
Suppression of apoptosis |
[23][24] |
Peroxidins I and II |
Cytoplasm and nucleus |
Antioxidant activity |
[25] |
Smad3 |
Cytoplasm |
Downregulation of E-cadherin expression, EMT |
[26][27] |
β-catenin |
Cytoplasm |
Translocation into nucleus and tumor cell invasion |
[28] |
STAT3 |
Cytoplasm |
Activation of JAK/STAT3 signaling and inflammatory responses |
[29] |
TAK1 |
Cytoplasm |
Activation of ADAM17 MMP enhances sIL-6R release and M2 macrophage differentiation |
[30] |
ERK1 |
Cytoplasm |
Activation of ERK1, proliferation, survival, and increased cell motility |
[31] |
AKT |
Cytoplasm |
Activation of AKT pathway, cell migration |
[32] |
This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics16010054