TISIDB

Summary
Symbol	HDAC3
Name	histone deacetylase 3
Aliases	HD3; RPD3-2; SMAP45
Chromosomal Location	5q31.1-q31.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Basic function annotation. > Subcellular Location, Domain and Function > Gene Ontology > KEGG and Reactome Pathway

> Subcellular Location, Domain and Function [ TOP ]
Subcellular Location	Nucleus Cytoplasm Cytoplasm, cytosol Note=Colocalizes with XBP1 and AKT1 in the cytoplasm (PubMed:25190803). Predominantly expressed in the nucleus in the presence of CCAR2.
Domain	PF00850 Histone deacetylase domain
Function	Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4), and some other non-histone substrates. Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Participates in the BCL6 transcriptional repressor activity by deacetylating the H3 'Lys-27' (H3K27) on enhancer elements, antagonizing EP300 acetyltransferase activity and repressing proximal gene expression. Probably participates in the regulation of transcription through its binding to the zinc-finger transcription factor YY1; increases YY1 repression activity. Required to repress transcription of the POU1F1 transcription factor. Acts as a molecular chaperone for shuttling phosphorylated NR2C1 to PML bodies for sumoylation (PubMed:21444723, PubMed:23911289). Contributes, together with XBP1 isoform 1, to the activation of NFE2L2-mediated HMOX1 transcription factor gene expression in a PI(3)K/mTORC2/Akt-dependent signaling pathway leading to endothelial cell (EC) survival under disturbed flow/oxidative stress (PubMed:25190803).

> Gene Ontology [ TOP ]
Biological Process	GO:0000226 microtubule cytoskeleton organization GO:0001933 negative regulation of protein phosphorylation GO:0006476 protein deacetylation GO:0006606 protein import into nucleus GO:0006913 nucleocytoplasmic transport GO:0007051 spindle organization GO:0007254 JNK cascade GO:0007623 circadian rhythm GO:0016570 histone modification GO:0016575 histone deacetylation GO:0017038 protein import GO:0031098 stress-activated protein kinase signaling cascade GO:0031647 regulation of protein stability GO:0031929 TOR signaling GO:0032006 regulation of TOR signaling GO:0032008 positive regulation of TOR signaling GO:0032386 regulation of intracellular transport GO:0032388 positive regulation of intracellular transport GO:0032872 regulation of stress-activated MAPK cascade GO:0032873 negative regulation of stress-activated MAPK cascade GO:0033157 regulation of intracellular protein transport GO:0034405 response to fluid shear stress GO:0034504 protein localization to nucleus GO:0035601 protein deacylation GO:0042306 regulation of protein import into nucleus GO:0042307 positive regulation of protein import into nucleus GO:0042326 negative regulation of phosphorylation GO:0042990 regulation of transcription factor import into nucleus GO:0042991 transcription factor import into nucleus GO:0042993 positive regulation of transcription factor import into nucleus GO:0043409 negative regulation of MAPK cascade GO:0044744 protein targeting to nucleus GO:0046328 regulation of JNK cascade GO:0046329 negative regulation of JNK cascade GO:0046822 regulation of nucleocytoplasmic transport GO:0046824 positive regulation of nucleocytoplasmic transport GO:0048511 rhythmic process GO:0051169 nuclear transport GO:0051170 nuclear import GO:0051222 positive regulation of protein transport GO:0051225 spindle assembly GO:0051403 stress-activated MAPK cascade GO:0070302 regulation of stress-activated protein kinase signaling cascade GO:0070303 negative regulation of stress-activated protein kinase signaling cascade GO:0070932 histone H3 deacetylation GO:0071498 cellular response to fluid shear stress GO:0090316 positive regulation of intracellular protein transport GO:0098732 macromolecule deacylation GO:1900180 regulation of protein localization to nucleus GO:1900182 positive regulation of protein localization to nucleus GO:1902532 negative regulation of intracellular signal transduction GO:1902593 single-organism nuclear import GO:1903533 regulation of protein targeting GO:1903829 positive regulation of cellular protein localization GO:1904589 regulation of protein import GO:1904591 positive regulation of protein import GO:1904951 positive regulation of establishment of protein localization
Molecular Function	GO:0003682 chromatin binding GO:0003714 transcription corepressor activity GO:0004407 histone deacetylase activity GO:0008134 transcription factor binding GO:0016810 hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds GO:0016811 hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides GO:0017136 NAD-dependent histone deacetylase activity GO:0019213 deacetylase activity GO:0030332 cyclin binding GO:0031078 histone deacetylase activity (H3-K14 specific) GO:0032041 NAD-dependent histone deacetylase activity (H3-K14 specific) GO:0033558 protein deacetylase activity GO:0034979 NAD-dependent protein deacetylase activity GO:0042826 histone deacetylase binding GO:0051059 NF-kappaB binding
Cellular Component	GO:0000118 histone deacetylase complex GO:0005819 spindle GO:0005874 microtubule GO:0005876 spindle microtubule GO:0017053 transcriptional repressor complex

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04919 Thyroid hormone signaling pathway
Reactome	R-HSA-5619507: Activation of HOX genes during differentiation R-HSA-5617472: Activation of anterior HOX genes in hindbrain development during early embryogenesis R-HSA-390471: Association of TriC/CCT with target proteins during biosynthesis R-HSA-1368108: BMAL1 R-HSA-390466: Chaperonin-mediated protein folding R-HSA-3247509: Chromatin modifying enzymes R-HSA-4839726: Chromatin organization R-HSA-400253: Circadian Clock R-HSA-2894862: Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants R-HSA-2644606: Constitutive Signaling by NOTCH1 PEST Domain Mutants R-HSA-1266738: Developmental Biology R-HSA-1643685: Disease R-HSA-5663202: Diseases of signal transduction R-HSA-535734: Fatty acid, triacylglycerol, and ketone body metabolism R-HSA-3214815: HDACs deacetylate histones R-HSA-1430728: Metabolism R-HSA-556833: Metabolism of lipids and lipoproteins R-HSA-392499: Metabolism of proteins R-HSA-1592230: Mitochondrial biogenesis R-HSA-2122947: NOTCH1 Intracellular Domain Regulates Transcription R-HSA-1368071: NR1D1 (REV-ERBA) represses gene expression R-HSA-1852241: Organelle biogenesis and maintenance R-HSA-1989781: PPARA activates gene expression R-HSA-391251: Protein folding R-HSA-1368082: RORA activates gene expression R-HSA-400206: Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha) R-HSA-162582: Signal Transduction R-HSA-157118: Signaling by NOTCH R-HSA-1980143: Signaling by NOTCH1 R-HSA-2894858: Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer R-HSA-2644602: Signaling by NOTCH1 PEST Domain Mutants in Cancer R-HSA-2644603: Signaling by NOTCH1 in Cancer R-HSA-166520: Signalling by NGF R-HSA-2151201: Transcriptional activation of mitochondrial biogenesis R-HSA-381340: Transcriptional regulation of white adipocyte differentiation R-HSA-193704: p75 NTR receptor-mediated signalling R-HSA-193670: p75NTR negatively regulates cell cycle via SC1

> KEGG and Reactome Pathway

[ TOP ]

KEGG

hsa04919 Thyroid hormone signaling pathway

Reactome

R-HSA-5619507: Activation of HOX genes during differentiation
R-HSA-5617472: Activation of anterior HOX genes in hindbrain development during early embryogenesis
R-HSA-390471: Association of TriC/CCT with target proteins during biosynthesis
R-HSA-1368108: BMAL1
R-HSA-390466: Chaperonin-mediated protein folding
R-HSA-3247509: Chromatin modifying enzymes
R-HSA-4839726: Chromatin organization
R-HSA-400253: Circadian Clock
R-HSA-2894862: Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-2644606: Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-1266738: Developmental Biology
R-HSA-1643685: Disease
R-HSA-5663202: Diseases of signal transduction
R-HSA-535734: Fatty acid, triacylglycerol, and ketone body metabolism
R-HSA-3214815: HDACs deacetylate histones
R-HSA-1430728: Metabolism
R-HSA-556833: Metabolism of lipids and lipoproteins
R-HSA-392499: Metabolism of proteins
R-HSA-1592230: Mitochondrial biogenesis
R-HSA-2122947: NOTCH1 Intracellular Domain Regulates Transcription
R-HSA-1368071: NR1D1 (REV-ERBA) represses gene expression
R-HSA-1852241: Organelle biogenesis and maintenance
R-HSA-1989781: PPARA activates gene expression
R-HSA-391251: Protein folding
R-HSA-1368082: RORA activates gene expression
R-HSA-400206: Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha)
R-HSA-162582: Signal Transduction
R-HSA-157118: Signaling by NOTCH
R-HSA-1980143: Signaling by NOTCH1
R-HSA-2894858: Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer
R-HSA-2644602: Signaling by NOTCH1 PEST Domain Mutants in Cancer
R-HSA-2644603: Signaling by NOTCH1 in Cancer
R-HSA-166520: Signalling by NGF
R-HSA-2151201: Transcriptional activation of mitochondrial biogenesis
R-HSA-381340: Transcriptional regulation of white adipocyte differentiation
R-HSA-193704: p75 NTR receptor-mediated signalling
R-HSA-193670: p75NTR negatively regulates cell cycle via SC1

Summary
Symbol	HDAC3
Name	histone deacetylase 3
Aliases	HD3; RPD3-2; SMAP45
Chromosomal Location	5q31.1-q31.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between HDAC3 and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.

> Text Mining

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Literatures describing the relation between HDAC3 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
27733359	Lymphoma	Inhibit immunity	HDAC3 loss-of-function rescued repression of these enhancers and corresponding genes, including MHC class II, and more profoundly suppressed CREBBP-mutant lymphomas in vitro and in vivo.
19430493	Ovarian carcinoma	Inhibit immunity (NK cell function)	Furthermore, by small interfering RNA-mediated knockdown and overexpression of HDAC1-3, we showed that HDAC3 is a repressor of ULBPs expression in epithelial cancer cells. Remarkably, TSA treatment caused the complete release of HDAC3 from the ULBP1-3 promoters.

Summary
Symbol	HDAC3
Name	histone deacetylase 3
Aliases	HD3; RPD3-2; SMAP45
Chromosomal Location	5q31.1-q31.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.

> High-throughput Screening

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Statistical results of HDAC3 in screening data sets for detecting immune reponses.

PMID	Screening System	Cancer Type	Cell Line	Data Set	Statistical Results	Relation to immunity
29301958	CRISPR-Cas9	melanoma	B16F10	Pmel-1 T cell	NA/NS	NA/NS
29301958	CRISPR-Cas9	melanoma	B16F10	OT-1 T cell	NA/NS	NA/NS
28783722	CRISPR-Cas9	melanoma	Mel624	2CT-CRISPR	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX+Anti-PD1	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX	NA/NS	NA/NS
25691366	RNAi	Breast cancer	MCF7	Luc-CTL assay	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Primary screen	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Secondary screen	NA/NS	NA/NS

Summary
Symbol	HDAC3
Name	histone deacetylase 3
Aliases	HD3; RPD3-2; SMAP45
Chromosomal Location	5q31.1-q31.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets. > Expression difference between responders and non-responders > Mutation difference between responders and non-responders

> Expression difference between responders and non-responders

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Points in the above scatter plot represent the expression difference of HDAC3 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	Log2 (Fold Change)	P value
1	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	14	12	0.153	0.358
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	0.121	0.957
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	0.18	0.91
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0.072	0.786
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-0.198	0.906
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0.415	0.849
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	-0.042	0.909
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	-0.095	0.952
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0.007	0.997
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	-0.103	0.954
11	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	2	0	0	1
12	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	2	8	0.222	0.934
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.07	0.205

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of HDAC3 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	0	0	0	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	0	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	7.4	1.4	6	0.177
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	7.4	1.7	5.7	0.231
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	0	0	0	1
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	0	0	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	0	0	0	1
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	6.2	-6.2	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	11.1	-11.1	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	0	0	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	0	0	0	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	0	0	0	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	0	0	0	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	0	1

Summary
Symbol	HDAC3
Name	histone deacetylase 3
Aliases	HD3; RPD3-2; SMAP45
Chromosomal Location	5q31.1-q31.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of HDAC3. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.

> Lymphocyte [ TOP ]

Summary
Symbol	HDAC3
Name	histone deacetylase 3
Aliases	HD3; RPD3-2; SMAP45
Chromosomal Location	5q31.1-q31.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of HDAC3. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by HDAC3. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	HDAC3
Name	histone deacetylase 3
Aliases	HD3; RPD3-2; SMAP45
Chromosomal Location	5q31.1-q31.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of HDAC3. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene. > Chemokine > Receptor

> Chemokine [ TOP ]

> Receptor [ TOP ]

Summary
Symbol	HDAC3
Name	histone deacetylase 3
Aliases	HD3; RPD3-2; SMAP45
Chromosomal Location	5q31.1-q31.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of HDAC3 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	HDAC3
Name	histone deacetylase 3
Aliases	HD3; RPD3-2; SMAP45
Chromosomal Location	5q31.1-q31.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between HDAC3 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	HDAC3
Name	histone deacetylase 3
Aliases	HD3; RPD3-2; SMAP45
Chromosomal Location	5q31.1-q31.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting HDAC3 collected from DrugBank database.

> Drugs from DrugBank database

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Details on drugs targeting HDAC3.

ID	Name	Drug Type	Targets	#Targets
DB02546	Vorinostat	Small Molecule	HDAC1, HDAC2, HDAC3, HDAC6, HDAC8	5
DB05015	Belinostat	Small Molecule	HDAC1, HDAC10, HDAC11, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, H ......	11
DB05223	Pracinostat	Small Molecule	HDAC1, HDAC2, HDAC3, HDAC6	4
DB06603	Panobinostat	Small Molecule	HDAC1, HDAC10, HDAC11, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, H ......	11
DB11830	Mocetinostat	Small Molecule	HDAC1, HDAC2, HDAC3	3

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