Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC6GUV3)

DOT Name	Histone deacetylase 3 (HDAC3)
Synonyms	HD3; EC 3.5.1.98; Protein deacetylase HDAC3; EC 3.5.1.-; Protein deacylase HDAC3; EC 3.5.1.-; RPD3-2; SMAP45
Gene Name	HDAC3
UniProt ID	HDAC3_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	4A69
EC Number	3.5.1.-; 3.5.1.98
Pfam ID	PF00850
Sequence	MAKTVAYFYDPDVGNFHYGAGHPMKPHRLALTHSLVLHYGLYKKMIVFKPYQASQHDMCR FHSEDYIDFLQRVSPTNMQGFTKSLNAFNVGDDCPVFPGLFEFCSRYTGASLQGATQLNN KICDIAINWAGGLHHAKKFEASGFCYVNDIVIGILELLKYHPRVLYIDIDIHHGDGVQEA FYLTDRVMTVSFHKYGNYFFPGTGDMYEVGAESGRYYCLNVPLRDGIDDQSYKHLFQPVI NQVVDFYQPTCIVLQCGADSLGCDRLGCFNLSIRGHGECVEYVKSFNIPLLVLGGGGYTV RNVARCWTYETSLLVEEAISEELPYSEYFEYFAPDFTLHPDVSTRIENQNSRQYLDQIRQ TIFENLKMLNHAPSVQIHDVPADLLTYDRTDEADAEERGPEENYSRPEAPNEFYDGDHDN DKESDVEI
Function	Histone deacetylase that catalyzes 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. Acts as a molecular chaperone for shuttling phosphorylated NR2C1 to PML bodies for sumoylation. 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. Regulates both the transcriptional activation and repression phases of the circadian clock in a deacetylase activity-independent manner. During the activation phase, promotes the accumulation of ubiquitinated BMAL1 at the E-boxes and during the repression phase, blocks FBXL3-mediated CRY1/2 ubiquitination and promotes the interaction of CRY1 and BMAL1. The NCOR1-HDAC3 complex regulates the circadian expression of the core clock gene BMAL1 and the genes involved in lipid metabolism in the liver. Also functions as a deacetylase for non-histone targets, such as KAT5, MEF2D, MAPK14, RARA and STAT3. Serves as a corepressor of RARA, mediating its deacetylation and repression, leading to inhibition of RARE DNA element binding. In association with RARA, plays a role in the repression of microRNA-10a and thereby in the inflammatory response. In addition to protein deacetylase activity, also acts as a protein-lysine deacylase by recognizing other acyl groups: catalyzes removal of (2E)-butenoyl (crotonyl) and 2-hydroxyisobutanoyl (2-hydroxyisobutyryl) acyl groups from lysine residues, leading to protein decrotonylation and de-2-hydroxyisobutyrylation, respectively. Catalyzes decrotonylation of MAPRE1/EB1.
Tissue Specificity	Widely expressed.
KEGG Pathway	Neutrophil extracellular trap formation (hsa04613 ) Thyroid hormone sig.ling pathway (hsa04919 ) Alcoholism (hsa05034 ) Viral carcinogenesis (hsa05203 )
Reactome Pathway	p75NTR negatively regulates cell cycle via SC1 (R-HSA-193670 ) PPARA activates gene expression (R-HSA-1989781 ) NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947 ) Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201 ) Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606 ) Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862 ) HDACs deacetylate histones (R-HSA-3214815 ) Notch-HLH transcription pathway (R-HSA-350054 ) Transcriptional regulation of white adipocyte differentiation (R-HSA-381340 ) Association of TriC/CCT with target proteins during biosynthesis (R-HSA-390471 ) Regulation of lipid metabolism by PPARalpha (R-HSA-400206 ) Circadian Clock (R-HSA-400253 ) Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472 ) RUNX2 regulates osteoblast differentiation (R-HSA-8940973 ) Regulation of PTEN gene transcription (R-HSA-8943724 ) Loss of MECP2 binding ability to the NCoR/SMRT complex (R-HSA-9022537 ) Regulation of MECP2 expression and activity (R-HSA-9022692 ) NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux (R-HSA-9029569 ) HCMV Early Events (R-HSA-9609690 ) STAT3 nuclear events downstream of ALK signaling (R-HSA-9701898 ) Cytoprotection by HMOX1 (R-HSA-9707564 ) Heme signaling (R-HSA-9707616 ) NR1D1 (REV-ERBA) represses gene expression (R-HSA-1368071 )

Molecular Interaction Atlas (MIA) of This DOT

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

23 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Histone deacetylase 3 (HDAC3).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Histone deacetylase 3 (HDAC3).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Histone deacetylase 3 (HDAC3).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Histone deacetylase 3 (HDAC3).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Histone deacetylase 3 (HDAC3).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Histone deacetylase 3 (HDAC3).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the activity of Histone deacetylase 3 (HDAC3).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine decreases the activity of Histone deacetylase 3 (HDAC3).	[8]
Marinol	DM70IK5	Approved	Marinol increases the expression of Histone deacetylase 3 (HDAC3).	[9]
Melatonin	DMKWFBT	Approved	Melatonin decreases the activity of Histone deacetylase 3 (HDAC3).	[10]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Histone deacetylase 3 (HDAC3).	[11]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Histone deacetylase 3 (HDAC3).	[12]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Histone deacetylase 3 (HDAC3).	[13]
MGCD-0103	DM726HX	Phase 2	MGCD-0103 decreases the expression of Histone deacetylase 3 (HDAC3).	[14]
AMEP	DMFELMQ	Phase 1	AMEP increases the expression of Histone deacetylase 3 (HDAC3).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Histone deacetylase 3 (HDAC3).	[16]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the activity of Histone deacetylase 3 (HDAC3).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Histone deacetylase 3 (HDAC3).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the activity of Histone deacetylase 3 (HDAC3).	[19]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Histone deacetylase 3 (HDAC3).	[15]
15-deoxy-Delta(12, 14)-prostaglandin J(2)	DM8VUX3	Investigative	15-deoxy-Delta(12, 14)-prostaglandin J(2) decreases the expression of Histone deacetylase 3 (HDAC3).	[20]
HONOKIOL	DMJWT3X	Investigative	HONOKIOL decreases the expression of Histone deacetylase 3 (HDAC3).	[10]
Oxalic Acid	DMLN2GQ	Investigative	Oxalic Acid increases the expression of Histone deacetylase 3 (HDAC3).	[21]
------------------------------------------------------------------------------------


⏷ Show the Full List of 23 Drug(s)

References

1	Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
2	Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. Blood. 2007 May 15;109(10):4450-60.
3	Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
4	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
5	Effects of chronic exposure to arsenic and estrogen on epigenetic regulatory genes expression and epigenetic code in human prostate epithelial cells. PLoS One. 2012;7(8):e43880. doi: 10.1371/journal.pone.0043880. Epub 2012 Aug 27.
6	Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
7	Effect of inhibitors of histone deacetylase on the induction of cell differentiation in murine and human erythroleukemia cell lines. Anticancer Drugs. 2005 Jul;16(6):635-43. doi: 10.1097/00001813-200507000-00008.
8	Carbamazepine is an inhibitor of histone deacetylases. Life Sci. 2005 May 13;76(26):3107-15. doi: 10.1016/j.lfs.2005.01.003.
9	Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
10	Targeting histone deacetylase-3 blocked epithelial-mesenchymal plasticity and metastatic dissemination in gastric cancer. Cell Biol Toxicol. 2023 Oct;39(5):1873-1896. doi: 10.1007/s10565-021-09673-2. Epub 2022 Jan 1.
11	Resveratrol-induced gene expression profiles in human prostate cancer cells. Cancer Epidemiol Biomarkers Prev. 2005 Mar;14(3):596-604. doi: 10.1158/1055-9965.EPI-04-0398.
12	Curcumin, both histone deacetylase and p300/CBP-specific inhibitor, represses the activity of nuclear factor kappa B and Notch 1 in Raji cells. Basic Clin Pharmacol Toxicol. 2007 Dec;101(6):427-33. doi: 10.1111/j.1742-7843.2007.00142.x. Epub 2007 Oct 9.
13	The Effects of Combinatorial Genistein and Sulforaphane in Breast Tumor Inhibition: Role in Epigenetic Regulation. Int J Mol Sci. 2018 Jun 13;19(6):1754. doi: 10.3390/ijms19061754.
14	Induction of USP17 by combining BET and HDAC inhibitors in breast cancer cells. Oncotarget. 2015 Oct 20;6(32):33623-35. doi: 10.18632/oncotarget.5601.
15	Glyphosate and AMPA Induce Alterations in Expression of Genes Involved in Chromatin Architecture in Human Peripheral Blood Mononuclear Cells (In Vitro). Int J Mol Sci. 2021 Mar 15;22(6):2966. doi: 10.3390/ijms22062966.
16	Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
17	A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression. Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8921-6. doi: 10.1073/pnas.132556899. Epub 2002 Jun 17.
18	Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
19	Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition. Proc Natl Acad Sci U S A. 2004 May 4;101(18):7199-204.
20	Anticancer effects of 15d-prostaglandin-J2 in wild-type and doxorubicin-resistant ovarian cancer cells: novel actions on SIRT1 and HDAC. PLoS One. 2011;6(9):e25192. doi: 10.1371/journal.pone.0025192. Epub 2011 Sep 21.
21	Butyric acid inhibits oxidative stress and inflammation injury in calcium oxalate nephrolithiasis by targeting CYP2C9. Food Chem Toxicol. 2023 Aug;178:113925. doi: 10.1016/j.fct.2023.113925. Epub 2023 Jul 4.