Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5L4RYX)

• DOT Name: Histone deacetylase 8 (HDAC8)
• Synonyms: HD8; EC 3.5.1.98; Protein deacetylase HDAC8; EC 3.5.1.-; Protein decrotonylase HDAC8; EC 3.5.1.-
• Gene Name: HDAC8
• Related Disease:
  Cornelia de Lange syndrome
  Cornelia de Lange syndrome 5
  Wilson-Turner syndrome
• UniProt ID: HDAC8_HUMAN
• PDB ID: 1T64 ; 1T67 ; 1T69 ; 1VKG ; 1W22 ; 2V5W ; 2V5X ; 3EW8 ; 3EWF ; 3EZP ; 3EZT ; 3F06 ; 3F07 ; 3F0R ; 3MZ3 ; 3MZ4 ; 3MZ6 ; 3MZ7 ; 3RQD ; 3SFF ; 3SFH ; 4QA0 ; 4QA1 ; 4QA2 ; 4QA3 ; 4QA4 ; 4QA5 ; 4QA6 ; 4QA7 ; 4RN0 ; 4RN1 ; 4RN2 ; 5BWZ ; 5D1B ; 5D1C ; 5D1D ; 5DC5 ; 5DC6 ; 5DC7 ; 5DC8 ; 5FCW ; 5THS ; 5THT ; 5THU ; 5THV ; 5VI6 ; 6HSK ; 6ODA ; 6ODB ; 6ODC ; 7JVU ; 7JVV ; 7JVW
• EC Number: 3.5.1.-; 3.5.1.98
• Pfam ID: PF00850
• Sequence:
  MEEPEEPADSGQSLVPVYIYSPEYVSMCDSLAKIPKRASMVHSLIEAYALHKQMRIVKPK
  VASMEEMATFHTDAYLQHLQKVSQEGDDDHPDSIEYGLGYDCPATEGIFDYAAAIGGATI
  TAAQCLIDGMCKVAINWSGGWHHAKKDEASGFCYLNDAVLGILRLRRKFERILYVDLDLH
  HGDGVEDAFSFTSKVMTVSLHKFSPGFFPGTGDVSDVGLGKGRYYSVNVPIQDGIQDEKY
  YQICESVLKEVYQAFNPKAVVLQLGADTIAGDPMCSFNMTPVGIGKCLKYILQWQLATLI
  LGGGGYNLANTARCWTYLTGVILGKTLSSEIPDHEFFTAYGPDYVLEITPSCRPDRNEPH
  RIQQILNYIKGNLKHVV
• Function: Histone deacetylase that catalyzes 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. Also involved in the deacetylation of cohesin complex protein SMC3 regulating release of cohesin complexes from chromatin. May play a role in smooth muscle cell contractility. In addition to protein deacetylase activity, also has protein-lysine deacylase activity: acts as a protein decrotonylase by mediating decrotonylation ((2E)-butenoyl) of histones.
• Tissue Specificity: Weakly expressed in most tissues. Expressed at higher level in heart, brain, kidney and pancreas and also in liver, lung, placenta, prostate and kidney.
• KEGG Pathway:
  Cell cycle (hsa04110)
  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)
  HDACs deacetylate histones (R-HSA-3214815)
  Notch-HLH transcription pathway (R-HSA-350054)
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cornelia de Lange syndrome	DISEQSXO	Definitive	X-linked	[1]
Cornelia de Lange syndrome 5	DISEXLJF	Strong	X-linked	[2]
Wilson-Turner syndrome	DISL3YW9	Supportive	X-linked	[3]

11 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 8 (HDAC8).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Histone deacetylase 8 (HDAC8).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Histone deacetylase 8 (HDAC8).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Histone deacetylase 8 (HDAC8).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Histone deacetylase 8 (HDAC8).	[8]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Histone deacetylase 8 (HDAC8).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Histone deacetylase 8 (HDAC8).	[11]
Berberine	DMC5Q8X	Phase 4	Berberine decreases the expression of Histone deacetylase 8 (HDAC8).	[12]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Histone deacetylase 8 (HDAC8).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Histone deacetylase 8 (HDAC8).	[15]
Oxalic Acid	DMLN2GQ	Investigative	Oxalic Acid increases the expression of Histone deacetylase 8 (HDAC8).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Histone deacetylase 8 (HDAC8).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Histone deacetylase 8 (HDAC8).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Histone deacetylase 8 (HDAC8).	[10]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Epigenetic control of skull morphogenesis by histone deacetylase 8. Genes Dev. 2009 Jul 15;23(14):1625-30. doi: 10.1101/gad.1809209.
• [3] X-exome sequencing identifies a HDAC8 variant in a large pedigree with X-linked intellectual disability, truncal obesity, gynaecomastia, hypogonadism and unusual face. J Med Genet. 2012 Aug;49(8):539-43. doi: 10.1136/jmedgenet-2012-100921.
• [4] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [10] 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.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Berberine acts as a putative epigenetic modulator by affecting the histone code. Toxicol In Vitro. 2016 Oct;36:10-17. doi: 10.1016/j.tiv.2016.06.004. Epub 2016 Jun 13.
• [13] 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.
• [14] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] 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.