Abstract proteins (co-repressor molecules) like NuRD, CoREST, Sin3A and

Abstract

Histone deacetylases (HDACs) are the members of
Histone deacetylase superfamily having four classes, namely Class I to IV with
nucleolar or cytoplasmic localization. Histone deacetylases (HDACs) are known
to play an important role in histone modification and thereby regulating gene
transcription. Out of four classes of HDACs, Class IV has a single member
HDAC11, and is thought to be homologous to Class I and II. HDAC 11 being the
only member is thought to be unique and a potent drug target for carcinomas.
According to Cancer Atlas database, it constitutes high mutations in many
cancer patients and thereby acting as the likely target for drug based cancer
therapy. Moreover, there are studies of HDAC11 playing role in immune tolerance
and as an epigenetic regulator in tissue specific manner but the basic
physiological mechanism is not yet known. In relation to cellular physiology,
it is known to interact with IL10 promoter and regulate its production in APCs.
Also the knockdown of HDAC11 gene led to G1 arrest of cells whereas
overexpression enhances the cell viability and decreases the apoptosis in MCL
cell lines. Thus it becomes important to understand the significance of the
HDAC11 as to why it is kept under a separate class and how it plays a role in
different cellular and disease physiological conditions. In this review, we
summarize the role of HDAC 11 as a novel biomarker in various patho-physiological
conditions and its functional significance in cellular physiology.

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Keywords: HDAC11,
repressor complex, cell survival

 

INTRODUCTION

 Histone deacetylases (HDACs) are the members
of Histone deacetylase superfamily along with acetylpolyamine amidohydrolases
and acetoin utilization protein HDAC family has four classes, namely Class I
(HDAC 1, 2, 3, 8) and are mostly nucleolar in origin. Class II (HDAC 4, 5, 6,
7, 9, 10) usually shuttles between nucleus and cytoplasm depending on their
phosphorylation states and are thought to be involved in regulation of
non-histone proteins also. Class III (Sirt 1 to 7) are the only class of family
dependent upon NAD+ for the activity unlike other classes which require Zn+ as
a cofactor. The Class IV has the only member HDAC 11 due its low structural
similarity with other HDACs

These class of enzymes
mediate the removal of the acetyl group from the ?-N-acetyl of lysine of
the histones in DNA that makes the histones tightly bind to DNA and thus heterochromatize
and repress the gene activity. But it is also known that apart from histone
proteins, HDACs also play role in non-histone deacetylase activity in complex
with other corepressor molecules.(PMID 19608861)HDACs
form part of the repressor complexes along with other proteins (co-repressor
molecules) like NuRD, CoREST, Sin3A and are involved in transcriptional
repression and chromatin remodeling.

Histone deacetylase
11(HDAC11) primarily located in nucleus, is a 347 amino acid long protein
sequence (39kDa) which shares its 9 deacetylase motifs with the other HDAC
classes I and II and an isoelectric point of 6.88. HDAC11 is encoded by 10
exons and the 5′ flanking region of the gene consists of a TATA and CCAT
box-less promoter with 1-kb CpG-island. It constitutes a catalytic domain at
the N-terminus having histone deacetylase activity shown to be inhibited by the
Trapoxin (TPA analogue). According to FISH studies, human HDAC11 gene is
located on chromosome 3p25. Moreover, this region is thought to be prone to
various mutations in different cancer types. It has been shown by Affinity
capture –MS and yeast two hybrid assay that it has 166 physical interaction(protein-protein
interactions) with related proteins out of which 151 are of high throughput (as
depicted in BioGRID­­3.4 database for human HDAC11). According to a
study, HDAC11 depletion is enough to cause cell death in various cancers like
prostrate, breast, colon, ovarian cancer and is thought to exhibit tumor-
selective effects (H.E Deubzer et al  PMID:
23024001).

 

 

 

Fig:
Predicted and known interactions based on database search (string and target
explorer).

 

STRUCTURE

The first cloning of HDAC11 was
done by Lin Gao et al, 2002. They observed the localization and
interaction of HDAC11 with other HDACs and found that it is primarily seen as a
repressor complex associated with HDAC6.

Another
study looked into the chromosomal organization and localization of the HDAC11 gene
and predicted few ( GATA-1, NFKB, AML-1a, STATx) putative transcription factor
binding sites in the 5’UTR of the HDAC11 gene sequence using TFSEARCH program
but did not proved it experimentally. Moroever, they have identified an
internal STS marker RH92585 within exon 9 of HDAC11. Also, within exons 5 and 7
of HDAC11 i.e. between amino acid residues 139 and 189 lies the histone
deacetylase family signature, found to be highly conserved in all HDACs. They
have also observed a 1kb long CpG island in the 5′ upstream of the promoter
sequence with the help of CPG software hosted by EMBL. (Sussane voelter M et
al, 2005)

HDAC11 crystal structure is not
yet known but some research group have designed homology based structures using
online tools for secondary structure analysis and model building database like
Rasmol. They have also validated the model by Ramachandran plot analysis (Samant LR, et al.,2015).

 

Fig:
Homology model of HDAC11 (S. Thangapandian et al, 2012)

Thangapandian S
et al (2012) has validated a homology-modeling based 3D protein structure of
hdac11 by using
one of the HDAC8 crystal structures, as being more closely related to classI
than to classII HDACs. Also they have identified
the amino acid specific for the maintenance of the integrity of the tunnel-like
active site conserved in all HDACs.This study also proved the phylogenetic
closeness of HDAC11 to HDAC8 and HDAC10.This model gives a reliable information
of structure for the receptor based drug- designing.  (PMID:23209570)

 

 

According to RCSB PDB the HDAC11
protein is mainly shown as one large deacetylase domain with a 143rd
amino acid as a putative active site. Our research group is mainly focused upon
the domain characterization of the hdac11 protein and its functional significance
as a separate single member of the class IV histone deacetylases in disease
pathological conditions.

 

FUNCTION:

HDAC11 being the only member
of the class IV histone deacetylase family of proteins, have some structural
features homologous to class I and II but functionally its altogether different
from other HDACs. It is highly expressed in mutated state in many tumorous
conditions. According to NIH data portal, approximately 98 cases have been
affected by 90 mutation across 19 projects. 
Uterine endometrial carcinoma cases having the highest mutation rate
i.e. 29. There are around 55 mutations of type frame shift, missense, and stop
gained in HDAC11 protein as observed in many cancer cases.

It is observed that knockdown of HDAC11 in
MCL cell lines downregulates cyclin D1, p21 and bcl-2, thence arrests the cells in G1
phase. On the other hand overexpression enhances the cell viability and
decreases apoptosis in MCL cell lines. HDAC11 is also known to regulate IL-10 gene
expression in myeloid cells (Eva Sahakian et al, 2014). It also plays role in
APCs and T-cell response (Villagra, Cheng et al, 2009). The expression and
functional role of HDAC11 is highly tissue specific. According to a study in
PETs (pancreatic endocrine tumors), no point mutations or deletions were
observed in HDAC11 indicating some tissue specificity (Daniel Lindeberg et al,
2007). It is also thought to be a promising target for the development of drugs
for inducing tolerance post clinical liver transplantation in gene therapy (Zheng-rong Lian
et al, 2010).

 

 In another study, Foxp3+ Tregs
deficient of HDAC11 showed elevated suppressive function. Further indicating that
development and testing of specific HDAC11 pharmacologic inhibitors will prove beneficial
for translational and immunological therapies (Huang J et al, 2017). Moreover
it is also depicted by some studies that specific targeting HDAC11 in cancerous
cells decreases the viability of the cells and lead them to apoptosis (Duebzer
et al).

 

HDAC11 inhibitors: There are various
inhibitors that act on hdac11 but are considered as PAN inhibitors as there are
no specific isoform selective hdac11 inhibitors available yet. MGCD0103 (mocetinostat)
is a class 1 inhibitor of hdac1, 2, 3and also inhibits hdac11 (under phase I/II
clinical trials). Reports suggested that selective blocking of hdac11 inhibits
growth of cancer cells and lead them to apoptosis. So there is need to
understand more about hdac11 domain architecture and its catalytic activity for
the designing of hdac11 specific inhibitors to be used as a chemotherapeutic
agent. Trichostatin, Quisinostat,
Panabinostat, Pracinostat, CUDC-101, BG45, Dacinostat are amongst the other
compounds inhibiting hdac11 activity.

 

 

Phylogenetic evolution of
HDAC11

HDACs are thought to be evolved from as
early as the prokaryotes. Though the HDAC11 like proteins are seen in only
eubacteria and higher eukaryotic organisms mostly. Yet there is no clear
homologue of hdac11 found so far. But according to multiple alignment and BLAST
data its structurally similar sequence is found in C.elegans (uncharacterized
protein) implying its significance to study its structure and functional role
using it as a model system. Its structural similar sequences are found in
eubacteria, plants, algae and higher metazoans describing its evolutionary
history (Valerie Ledent et al, 2006). It is predicted via phyletic distribution
of HDAC11 related proteins that it has undergo gene duplication followed by
horizontal gene transfer possibly during evolution. Though the donor and
acceptor species have not been explored yet. In fig: we show the phyletic distribution
of human hdac11 related similar sequences.

 

 

SUMMARY

All HDACs has the histone deacetylase
domain which makes it a functional part of repressor complex thereby involved
in gene regulation. Moreover, in nature if all HDACs had the same function,
then there would be no need of other HDACs. Amongst 18 HDACs, HDAC11 shows low
structural similarity with the rest of them, indicating some different role for
its presence inside the cell specifically nucleus. Our lab is interested in
investigating the significance of HDAC11 in cell when already cell is loaded
with various repressor molecules. Moreover, there are a lot of mutation
reported in HDAC11 in cancer patients all over the world implying its role in
tumorigenesis. Additionally, its tissue specific function in most of the
disease conditions makes it a novel target for drug discovery in future.

 

FUTURE PERSPECTIVES

 

Hdac11 is known for its variable
functioning in different cell specific manner. Mostly it regulates cell cycle
progression in cancer cells and lead them to apoptosis. There is no effect of
change in hdac11 in normal cells. Thus it becomes a novel drug target for
chemotherapy. It is also important to explore the basic structure function
relationship of this molecule to have a better understanding of its role in
cells. Our group aims to study the architecture of this gene and how it has
been evolved as a separate class in HDAC family.

 

 

 

 

 

 

 

 

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