Site Loader
Rock Street, San Francisco


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.

We Will Write a Custom Essay Specifically
For You For Only $13.90/page!

order now


Keywords: HDAC11,
repressor complex, cell survival



 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:




Predicted and known interactions based on database search (string and target



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.

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).


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.



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

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.




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.




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.










1)Gao L, Cueto MA, Asselbergs F, Atadja P. Cloning and

characterization of HDAC11, a novel member of the human
histone deacetylase

family. J Biol Chem. 2002 Jul 12;277(28):25748-55. Epub 2002
Apr 10. PubMed PMID:



 2)Deubzer HE, Schier MC, Oehme I, Lodrini M,
Haendler B, Sommer A, Witt O.

HDAC11 is
a novel drug target in carcinomas. Int J Cancer. 2013 May

doi: 10.1002/ijc.27876. Epub 2012 Oct 25. PubMed PMID: 23024001.


3)Samant LR, Sangar VC, Gulamaliwala A and Chowdhary AS:
Computational Modelling and Functional Characterization of HDAC-11. Int J Pharm
Sci Res 2015; 6(4): 1727-35.doi: 10.13040/IJPSR.0975-8232.6(4).1727-35.


4) Choudhary
C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M (Aug
2009). “Lysine acetylation targets protein complexes
and co-regulates major cellular functions”. Science. 325 (5942): 834–40. PMID 19608861. doi:10.1126/science.1175371.

Sundarapandian & John, Shalini & Lee, Yuno & Arulalapperumal,
Venkatesh & Lee, Keun Woo. (2012). Molecular Modeling Study on Tunnel
Behavior in Different Histone Deacetylase Isoforms. PloS one. 7. e49327.

J, Wang L, Dahiya S, Beier UH, Han R, Samanta A, Bergman J, Sotomayor EM, Seto
E, Kozikowski AP, Hancock WW. Histone/protein deacetylase 11 targeting promotes
Foxp3+ Treg function. Sci Rep. 2017 Aug 17;7(1):8626. doi:10.1038/s41598-017-09211-3.
PubMed PMID: 28819166; PubMed Central PMCID:PMC5561267.


7) 1: Villagra A, Cheng F, Wang HW, Suarez I, Glozak M, Maurin M, Nguyen D, Wright

KL, Atadja PW, Bhalla K, Pinilla-Ibarz J, Seto
E, Sotomayor EM. The histone

deacetylase HDAC11 regulates the expression of
interleukin 10 and immune

tolerance. Nat Immunol. 2009 Jan;10(1):92-100.
doi: 10.1038/ni.1673. Epub 2008

Nov 16. Erratum in: Nat Immunol. 2009
Jun;10(6):665. PubMed PMID: 19011628;

PubMed Central PMCID: PMC3925685.


8) Voelter-Mahlknecht S, Ho AD, Mahlknecht U. Chromosomal organization andlocalization of the novel class IV human histone deacetylase 11 gene. Int J MolMed. 2005 Oct;16(4):589-98. PubMed PMID: 16142391.


9) Sahakian E, Powers JJ, Chen J, Deng SL, Cheng F, Distler A, Woods DM,Rock-Klotz J, Sodre AL, Youn JI, Woan KV, Villagra A, Gabrilovich D, SotomayorEM, Pinilla-Ibarz J. Histone deacetylase 11: A novel epigenetic regulator ofmyeloid derived suppressor cell expansion and function. Mol Immunol. 2015Feb;63(2):579-85. doi: 10.1016/j.molimm.2014.08.002. Epub 2014 Aug 23. PubMedPMID: 25155994; PubMed Central PMCID: PMC4252813.


10) Haberland M, Montgomery RL, Olson EN. The many roles of histone deacetylasesin development and physiology: implications for disease and therapy. Nat RevGenet. 2009 Jan;10(1):32-42. doi: 10.1038/nrg2485. Review. PubMed PMID: 19065135;PubMed Central PMCID: PMC3215088


11) Bagui TK, Sharma SS, Ma L, Pledger WJ. Proliferative status regulates HDAC11mRNA abundance in nontransformed fibroblasts. Cell Cycle. 2013 Nov1;12(21):3433-41. doi: 10.4161/cc.26433. Epub 2013 Sep 18. PubMed PMID: 24047695;PubMed Central PMCID: PMC3895431.


12) Mukherjee S, Mukherjee B, Mukhopadhyay R, Naskar K, Sundar S, Dujardin JC, RoyS. Imipramine exploits histone deacetylase 11 to increase the IL-12/IL-10 ratioin macrophages infected with antimony-resistant Leishmania donovani and clearsorgan parasites in experimental infection. J Immunol. 2014 Oct 15;193(8):4083-94.doi: 10.4049/jimmunol.1400710. Epub 2014 Sep 12. PubMed PMID: 25217162.


13) Lin L, Hou J, Ma F, Wang P, Liu X, Li N, Wang J, Wang Q, Cao X. Type I IFN inhibits innate IL-10 production in macrophages through histone deacetylase 11 by downregulating microRNA-145. J Immunol. 2013 Oct 1;191(7):3896-904. doi: 10.4049/jimmunol.1203450. Epub 2013 Aug 26. PubMed PMID: 23980205.


14) Buglio D, Khaskhely NM, Voo KS, Martinez-Valdez H, Liu YJ, Younes A. HDAC11plays an essential role in regulating OX40 ligand expression in Hodgkin lymphoma.Blood. 2011 Mar 10;117(10):2910-7. doi: 10.1182/blood-2010-08-303701. Epub 2011 Jan 14. Erratum in: Blood. 2014 Jul 17;124(3):464-5. PubMed PMID: 21239696;PubMed Central PMCID: PMC3062301 15) de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J.2003 Mar 15;370(Pt 3):737-49. Review. PubMed PMID: 12429021; PubMed Central PMCID: PMC1223209. 16) Ledent V, Vervoort M. Comparative genomics of the class 4 histone deacetylase family indicates a complex evolutionary history. BMC Biol. 2006 Aug 2;4:24.PubMed PMID: 16884538; PubMed Central PMCID: PMC1555614. 17) West AC, Johnstone RW. New and emerging HDAC inhibitors for cancer treatment. The Journal of Clinical Investigation. 2014;124(1):30-39. doi:10.1172/JCI69738. 18) Yanginlar C, Logie C. HDAC11 is a regulator of diverse immune functions.Biochim Biophys Acta. 2017 Dec 6;1861(1):54-59. doi:10.1016/j.bbagrm.2017.12.002. Epub ahead of print Review. PubMed PMID:290222071.19) Blixt NC, Faulkner BK, Astleford K, Lelich R, Schering J, Spencer E,Gopalakrishnan R, Jensen ED, Mansky KC. Class II and IV HDACs function asinhibitors of osteoclast differentiation. PLoS One. 2017 Sep 27;12(9):e0185441.doi: 10.1371/journal.pone.0185441. eCollection 2017. PubMed PMID: 28953929;PubMed Central PMCID: PMC5617211.  20) Byun SK, An TH, Son MJ, Lee DS, Kang HS, Lee EW, Han BS, Kim WK, Bae KH, Oh KJ, Lee SC. HDAC11 Inhibits Myoblast Differentiation through Repression of MyoD-Dependent Transcription. Mol Cells. 2017 Sep 30;40(9):667-676. doi:10.14348/molcells.2017.0116. Epub 2017 Sep 20. PubMed PMID: 28927261; PubMed Central PMCID: PMC5638774. 21) Chen J, Sahakian E, Powers J, Lienlaf M, Perez-Villarroel P, Knox T, Villagra A. Functional Analysis of Histone Deacetylase 11 (HDAC11). Methods Mol Biol.2016;1436:147-65. doi: 10.1007/978-1-4939-3667-0_11. PubMed PMID: 27246214. 22) Cheng F, Lienlaf M, Perez-Villarroel P, Wang HW, Lee C, Woan K, Woods D, Knox T, Bergman J, Pinilla-Ibarz J, Kozikowski A, Seto E, Sotomayor EM, Villagra A. Divergent roles of histone deacetylase 6 (HDAC6) and histone deacetylase 11 (HDAC11) on the transcriptional regulation of IL10 in antigen presenting cells. Mol Immunol. 2014 Jul;60(1):44-53. doi: 10.1016/j.molimm.2014.02.019. Epub 2014 Apr 18. PubMed PMID: 24747960; PubMed Central PMCID: PMC4020151.  23) Mrug M, Sanders PW. Beware the low HDAC11: males at risk for ischemic kidney injury. Am J Physiol Renal Physiol. 2013 Oct 1;305(7):F973-4. doi:10.1152/ajprenal.00308.2013. Epub 2013 Jul 24. PubMed PMID: 23884138; PubMed Central PMCID: PMC3798743. 24) Kim JI, Jung KJ, Jang HS, Park KM. Gender-specific role of HDAC11 in kidney ischemia- and reperfusion-induced PAI-1 expression and injury. Am J Physiol Renal Physiol. 2013 Jul 1;305(1):F61-70 doi:10.1152/ajprenal.00015.2013. Epub 2013 May 8. PubMed PMID: 23657855. 25) Lian ZR, Xu YF, Wang XB, Gong JP, Liu ZJ. Suppression of histone deacetylase 11 promotes expression of IL-10 in Kupffer cells and induces tolerance following orthotopic liver transplantation in rats. J Surg Res. 2012 May 15;174(2):359-68. doi: 10.1016/j.jss.2010.12.035. Epub 2011 Jan 26. PubMed PMID: 21392795. 26) Wong PG, Glozak MA, Cao TV, Vaziri C, Seto E, Alexandrow M. Chromatinunfolding by Cdt1 regulates MCM loading via opposing functions of HBO1 andHDAC11-geminin. Cell Cycle. 2010 Nov 1;9(21):4351-63. Epub 2010 Nov 11. PubMed PMID: 20980834; PubMed Central PMCID: PMC3055186. 27) Park SW, Kim HS, Yoo NJ, Lee SH. Mutational analysis of mononucleotide repeats in HDAC4, 5, 6, 7, 9 and 11 genes in gastric and colorectal carcinomas with microsatellite instability. Acta Oncol. 2011 Feb;50(2):317-8. doi:10.3109/0284186X.2010.504229. Epub 2010 Sep 15. PubMed PMID: 20843176. 28) Fournel M, Bonfils C, Hou Y, Yan PT, Trachy-Bourget MC, Kalita A, Liu J, Lu AH, Zhou NZ, Robert MF, Gillespie J, Wang JJ, Ste-Croix H, Rahil J, Lefebvre S, Moradei O, Delorme D, Macleod AR, Besterman JM, Li Z. MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumoractivity in vitro and in vivo. Mol Cancer Ther. 2008 Apr;7(4):759-68. doi:10.1158/1535-7163.MCT-07-2026. PubMed PMID: 18413790. 29) Lindberg D, Akerström G, Westin G. Mutational analyses of WNT7A and HDAC11 as candidate tumour suppressor genes in sporadic malignant pancreatic endocrinetumours. Clin Endocrinol (Oxf). 2007 Jan;66(1):110-4. PubMed PMID: 17201809. 30) Jagirdar R, Drexel M, Kirchmair E, Tasan RO, Sperk G. Rapid changes inexpression of class I and IV histone deacetylases during epileptogenesis in mousemodels of temporal lobe epilepsy. Exp Neurol. 2015 Nov;273:92-104. doi:10.1016/j.expneurol.2015.07.026. Epub 2015 Jul 31. Erratum in: Exp Neurol. 2016Apr;278:144. PubMed PMID: 26238735.   




Post Author: admin


I'm Dora!

Would you like to get a custom essay? How about receiving a customized one?

Check it out