Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ3P0XA)

• DOT Name: Histone deacetylase 7 (HDAC7)
• Synonyms: HD7; EC 3.5.1.98; Histone deacetylase 7A; HD7a
• Gene Name: HDAC7
• UniProt ID: HDAC7_HUMAN
• PDB ID: 3C0Y; 3C0Z; 3C10; 3ZNR; 3ZNS
• EC Number: 3.5.1.98
• Pfam ID: PF00850
• Sequence:
  MDLRVGQRPPVEPPPEPTLLALQRPQRLHHHLFLAGLQQQRSVEPMRLSMDTPMPELQVG
  PQEQELRQLLHKDKSKRSAVASSVVKQKLAEVILKKQQAALERTVHPNSPGIPYRTLEPL
  ETEGATRSMLSSFLPPVPSLPSDPPEHFPLRKTVSEPNLKLRYKPKKSLERRKNPLLRKE
  SAPPSLRRRPAETLGDSSPSSSSTPASGCSSPNDSEHGPNPILGSEALLGQRLRLQETSV
  APFALPTVSLLPAITLGLPAPARADSDRRTHPTLGPRGPILGSPHTPLFLPHGLEPEAGG
  TLPSRLQPILLLDPSGSHAPLLTVPGLGPLPFHFAQSLMTTERLSGSGLHWPLSRTRSEP
  LPPSATAPPPPGPMQPRLEQLKTHVQVIKRSAKPSEKPRLRQIPSAEDLETDGGGPGQVV
  DDGLEHRELGHGQPEARGPAPLQQHPQVLLWEQQRLAGRLPRGSTGDTVLLPLAQGGHRP
  LSRAQSSPAAPASLSAPEPASQARVLSSSETPARTLPFTTGLIYDSVMLKHQCSCGDNSR
  HPEHAGRIQSIWSRLQERGLRSQCECLRGRKASLEELQSVHSERHVLLYGTNPLSRLKLD
  NGKLAGLLAQRMFVMLPCGGVGVDTDTIWNELHSSNAARWAAGSVTDLAFKVASRELKNG
  FAVVRPPGHHADHSTAMGFCFFNSVAIACRQLQQQSKASKILIVDWDVHHGNGTQQTFYQ
  DPSVLYISLHRHDDGNFFPGSGAVDEVGAGSGEGFNVNVAWAGGLDPPMGDPEYLAAFRI
  VVMPIAREFSPDLVLVSAGFDAAEGHPAPLGGYHVSAKCFGYMTQQLMNLAGGAVVLALE
  GGHDLTAICDASEACVAALLGNRVDPLSEEGWKQKPNLNAIRSLEAVIRVHSKYWGCMQR
  LASCPDSWVPRVPGADKEEVEAVTALASLSVGILAEDRPSEQLVEEEEPMNL
• Function: Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). 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. Involved in muscle maturation by repressing transcription of myocyte enhancer factors such as MEF2A, MEF2B and MEF2C. During muscle differentiation, it shuttles into the cytoplasm, allowing the expression of myocyte enhancer factors. May be involved in Epstein-Barr virus (EBV) latency, possibly by repressing the viral BZLF1 gene. Positively regulates the transcriptional repressor activity of FOXP3. Serves as a corepressor of RARA, causing its deacetylation and 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.
• KEGG Pathway:
  Neutrophil extracellular trap formation (hsa04613)
  Alcoholism (hsa05034)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)
  Notch-HLH transcription pathway (R-HSA-350054)
  Regulation of PTEN gene transcription (R-HSA-8943724)
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Histone deacetylase 7 (HDAC7).	[1]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Histone deacetylase 7 (HDAC7).	[2]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Histone deacetylase 7 (HDAC7).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Histone deacetylase 7 (HDAC7).	[4]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Histone deacetylase 7 (HDAC7).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine decreases the activity of Histone deacetylase 7 (HDAC7).	[7]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Histone deacetylase 7 (HDAC7).	[8]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Histone deacetylase 7 (HDAC7).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Histone deacetylase 7 (HDAC7).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Histone deacetylase 7 (HDAC7).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Histone deacetylase 7 (HDAC7).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Histone deacetylase 7 (HDAC7).	[13]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Histone deacetylase 7 (HDAC7).	[5]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Histone deacetylase 7 (HDAC7).	[5]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Histone deacetylase 7 (HDAC7).	[5]

References

• [1] Valproic acid, but not levetiracetam, selectively decreases HDAC7 and HDAC2 expression in human ovarian cancer cells. Toxicol Lett. 2014 Jan 13;224(2):225-32. doi: 10.1016/j.toxlet.2013.10.035. Epub 2013 Nov 5.
• [2] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [3] 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.
• [4] 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.
• [5] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [6] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [7] Carbamazepine is an inhibitor of histone deacetylases. Life Sci. 2005 May 13;76(26):3107-15. doi: 10.1016/j.lfs.2005.01.003.
• [8] Estrogen receptor alpha (ER)-mediated coregulator binding and gene expression discriminates the toxic ER agonist diethylstilbestrol (DES) from the endogenous ER agonist 17-estradiol (E2). Cell Biol Toxicol. 2020 Oct;36(5):417-435. doi: 10.1007/s10565-020-09516-6. Epub 2020 Feb 22.
• [9] Prenatal nicotinic exposure suppresses fetal adrenal steroidogenesis via steroidogenic factor 1 (SF-1) deacetylation. Toxicol Appl Pharmacol. 2014 Jun 15;277(3):231-41.
• [10] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [11] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [12] 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.
• [13] Genome-Wide Analysis of Low Dose Bisphenol-A (BPA) Exposure in Human Prostate Cells. Curr Genomics. 2019 May;20(4):260-274. doi: 10.2174/1389202920666190603123040.