Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQNGD32)

• DOT Name: Histone deacetylase 4 (HDAC4)
• Synonyms: HD4; EC 3.5.1.98
• Gene Name: HDAC4
• Related Disease:
  2q37 microdeletion syndrome
  Neurodevelopmental disorder with central hypotonia and dysmorphic facies
• UniProt ID: HDAC4_HUMAN
• PDB ID: 2H8N; 2O94; 2VQJ; 2VQM; 2VQO; 2VQQ; 2VQV; 2VQW; 3UXG; 3UZD; 3V31; 4CBT; 4CBY; 5A2S; 5ZOO; 5ZOP; 6FYZ; 7XUZ
• EC Number: 3.5.1.98
• Pfam ID: PF12203 ; PF00850
• Sequence:
  MSSQSHPDGLSGRDQPVELLNPARVNHMPSTVDVATALPLQVAPSAVPMDLRLDHQFSLP
  VAEPALREQQLQQELLALKQKQQIQRQILIAEFQRQHEQLSRQHEAQLHEHIKQQQEMLA
  MKHQQELLEHQRKLERHRQEQELEKQHREQKLQQLKNKEKGKESAVASTEVKMKLQEFVL
  NKKKALAHRNLNHCISSDPRYWYGKTQHSSLDQSSPPQSGVSTSYNHPVLGMYDAKDDFP
  LRKTASEPNLKLRSRLKQKVAERRSSPLLRRKDGPVVTALKKRPLDVTDSACSSAPGSGP
  SSPNNSSGSVSAENGIAPAVPSIPAETSLAHRLVAREGSAAPLPLYTSPSLPNITLGLPA
  TGPSAGTAGQQDAERLTLPALQQRLSLFPGTHLTPYLSTSPLERDGGAAHSPLLQHMVLL
  EQPPAQAPLVTGLGALPLHAQSLVGADRVSPSIHKLRQHRPLGRTQSAPLPQNAQALQHL
  VIQQQHQQFLEKHKQQFQQQQLQMNKIIPKPSEPARQPESHPEETEEELREHQALLDEPY
  LDRLPGQKEAHAQAGVQVKQEPIESDEEEAEPPREVEPGQRQPSEQELLFRQQALLLEQQ
  RIHQLRNYQASMEAAGIPVSFGGHRPLSRAQSSPASATFPVSVQEPPTKPRFTTGLVYDT
  LMLKHQCTCGSSSSHPEHAGRIQSIWSRLQETGLRGKCECIRGRKATLEELQTVHSEAHT
  LLYGTNPLNRQKLDSKKLLGSLASVFVRLPCGGVGVDSDTIWNEVHSAGAARLAVGCVVE
  LVFKVATGELKNGFAVVRPPGHHAEESTPMGFCYFNSVAVAAKLLQQRLSVSKILIVDWD
  VHHGNGTQQAFYSDPSVLYMSLHRYDDGNFFPGSGAPDEVGTGPGVGFNVNMAFTGGLDP
  PMGDAEYLAAFRTVVMPIASEFAPDVVLVSSGFDAVEGHPTPLGGYNLSARCFGYLTKQL
  MGLAGGRIVLALEGGHDLTAICDASEACVSALLGNELDPLPEKVLQQRPNANAVRSMEKV
  MEIHSKYWRCLQRTTSTAGRSLIEAQTCENEEAETVTAMASLSVGVKPAEKRPDEEPMEE
  EPPL
• 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 via its interaction with the myocyte enhancer factors such as MEF2A, MEF2C and MEF2D. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer. Deacetylates HSPA1A and HSPA1B at 'Lys-77' leading to their preferential binding to co-chaperone STUB1.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Apelin sig.ling pathway (hsa04371)
  Neutrophil extracellular trap formation (hsa04613)
  Alcoholism (hsa05034)
  Viral carcinogenesis (hsa05203)
  MicroR.s in cancer (hsa05206)
• Reactome Pathway:
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  Notch-HLH transcription pathway (R-HSA-350054)
  SUMOylation of intracellular receptors (R-HSA-4090294)
  SUMOylation of chromatin organization proteins (R-HSA-4551638)
  RUNX2 regulates chondrocyte maturation (R-HSA-8941284)
  RUNX3 regulates p14-ARF (R-HSA-8951936)
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
2q37 microdeletion syndrome	DISZYHCB	Definitive	Autosomal dominant	[1]
Neurodevelopmental disorder with central hypotonia and dysmorphic facies	DIS2S8FC	Strong	Autosomal dominant	[2]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Histone deacetylase 4 (HDAC4) affects the response to substance of Methotrexate.	[23]
Etoposide	DMNH3PG	Approved	Histone deacetylase 4 (HDAC4) affects the response to substance of Etoposide.	[23]
Mitoxantrone	DMM39BF	Approved	Histone deacetylase 4 (HDAC4) affects the response to substance of Mitoxantrone.	[23]
NAPQI	DM8F5LR	Investigative	Histone deacetylase 4 (HDAC4) affects the response to substance of NAPQI.	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Histone deacetylase 4 (HDAC4).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Histone deacetylase 4 (HDAC4).	[8]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Histone deacetylase 4 (HDAC4).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Histone deacetylase 4 (HDAC4).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Histone deacetylase 4 (HDAC4).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Histone deacetylase 4 (HDAC4).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Histone deacetylase 4 (HDAC4).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Histone deacetylase 4 (HDAC4).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Histone deacetylase 4 (HDAC4).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Histone deacetylase 4 (HDAC4).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Histone deacetylase 4 (HDAC4).	[10]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Histone deacetylase 4 (HDAC4).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Histone deacetylase 4 (HDAC4).	[13]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Histone deacetylase 4 (HDAC4).	[14]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Histone deacetylase 4 (HDAC4).	[15]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Histone deacetylase 4 (HDAC4).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Histone deacetylase 4 (HDAC4).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Histone deacetylase 4 (HDAC4).	[18]
Chlamydocin	DM89DQP	Preclinical	Chlamydocin decreases the activity of Histone deacetylase 4 (HDAC4).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Histone deacetylase 4 (HDAC4).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Histone deacetylase 4 (HDAC4).	[22]

References

• [1] Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems. Am J Hum Genet. 2010 Aug 13;87(2):219-28. doi: 10.1016/j.ajhg.2010.07.011.
• [2] Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome. HGG Adv. 2021 Jan 14;2(1):100015. doi: 10.1016/j.xhgg.2020.100015.
• [3] 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.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [9] Multifaceted preventive effects of single agent quercetin on a human prostate adenocarcinoma cell line (PC-3): implications for nutritional transcriptomics and multi-target therapy. Med Oncol. 2011 Dec;28(4):1395-404. doi: 10.1007/s12032-010-9603-3. Epub 2010 Jul 2.
• [10] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [11] Transcriptional profiling of MCF7 breast cancer cells in response to 5-Fluorouracil: relationship with cell cycle changes and apoptosis, and identification of novel targets of p53. Int J Cancer. 2006 Sep 1;119(5):1164-75.
• [12] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [13] Dexamethasone controls aryl hydrocarbon receptor (AhR)-mediated CYP1A1 and CYP1A2 expression and activity in primary cultures of human hepatocytes. Chem Biol Interact. 2009 May 15;179(2-3):288-96.
• [14] Bortezomib induces caspase-dependent apoptosis in Hodgkin lymphoma cell lines and is associated with reduced c-FLIP expression: a gene expression profiling study with implications for potential combination therapies. Leuk Res. 2008 Feb;32(2):275-85. doi: 10.1016/j.leukres.2007.05.024. Epub 2007 Jul 19.
• [15] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [16] Novel carbocyclic curcumin analog CUR3d modulates genes involved in multiple apoptosis pathways in human hepatocellular carcinoma cells. Chem Biol Interact. 2015 Dec 5;242:107-22.
• [17] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [18] 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.
• [19] 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.
• [20] Chlamydocin analogs bearing carbonyl group as possible ligand toward zinc atom in histone deacetylases. Bioorg Med Chem. 2006 May 15;14(10):3438-46. doi: 10.1016/j.bmc.2005.12.063. Epub 2006 Jan 24.
• [21] Epigenetic changes and disturbed neural development in a human embryonic stem cell-based model relating to the fetal valproate syndrome. Hum Mol Genet. 2012 Sep 15;21(18):4104-14. doi: 10.1093/hmg/dds239. Epub 2012 Jun 20.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [24] Acetaminophen-NAPQI hepatotoxicity: a cell line model system genome-wide association study. Toxicol Sci. 2011 Mar;120(1):33-41. doi: 10.1093/toxsci/kfq375. Epub 2010 Dec 22.