Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9W9MXQ)

• DOT Name: Histone deacetylase 6 (HDAC6)
• Synonyms: HD6; EC 3.5.1.98; Protein deacetylase HDAC6; EC 3.5.1.-; Tubulin-lysine deacetylase HDAC6; EC 3.5.1.-
• Gene Name: HDAC6
• Related Disease: X-linked dominant chondrodysplasia, Chassaing-Lacombe type
• UniProt ID: HDAC6_HUMAN
• PDB ID: 3C5K; 3GV4; 3PHD; 5B8D; 5EDU; 5KH3; 5KH7; 5KH9; 5WBN; 5WPB; 6CE6; 6CE8; 6CEA; 6CEC; 6CED; 6CEE; 6CEF; 7ZYU; 8G43; 8G44; 8G45
• EC Number: 3.5.1.-; 3.5.1.98
• Pfam ID: PF00850 ; PF02148
• Sequence:
  MTSTGQDSTTTRQRRSRQNPQSPPQDSSVTSKRNIKKGAVPRSIPNLAEVKKKGKMKKLG
  QAMEEDLIVGLQGMDLNLEAEALAGTGLVLDEQLNEFHCLWDDSFPEGPERLHAIKEQLI
  QEGLLDRCVSFQARFAEKEELMLVHSLEYIDLMETTQYMNEGELRVLADTYDSVYLHPNS
  YSCACLASGSVLRLVDAVLGAEIRNGMAIIRPPGHHAQHSLMDGYCMFNHVAVAARYAQQ
  KHRIRRVLIVDWDVHHGQGTQFTFDQDPSVLYFSIHRYEQGRFWPHLKASNWSTTGFGQG
  QGYTINVPWNQVGMRDADYIAAFLHVLLPVALEFQPQLVLVAAGFDALQGDPKGEMAATP
  AGFAQLTHLLMGLAGGKLILSLEGGYNLRALAEGVSASLHTLLGDPCPMLESPGAPCRSA
  QASVSCALEALEPFWEVLVRSTETVERDNMEEDNVEESEEEGPWEPPVLPILTWPVLQSR
  TGLVYDQNMMNHCNLWDSHHPEVPQRILRIMCRLEELGLAGRCLTLTPRPATEAELLTCH
  SAEYVGHLRATEKMKTRELHRESSNFDSIYICPSTFACAQLATGAACRLVEAVLSGEVLN
  GAAVVRPPGHHAEQDAACGFCFFNSVAVAARHAQTISGHALRILIVDWDVHHGNGTQHMF
  EDDPSVLYVSLHRYDHGTFFPMGDEGASSQIGRAAGTGFTVNVAWNGPRMGDADYLAAWH
  RLVLPIAYEFNPELVLVSAGFDAARGDPLGGCQVSPEGYAHLTHLLMGLASGRIILILEG
  GYNLTSISESMAACTRSLLGDPPPLLTLPRPPLSGALASITETIQVHRRYWRSLRVMKVE
  DREGPSSSKLVTKKAPQPAKPRLAERMTTREKKVLEAGMGKVTSASFGEESTPGQTNSET
  AVVALTQDQPSEAATGGATLAQTISEAAIGGAMLGQTTSEEAVGGATPDQTTSEETVGGA
  ILDQTTSEDAVGGATLGQTTSEEAVGGATLAQTTSEAAMEGATLDQTTSEEAPGGTELIQ
  TPLASSTDHQTPPTSPVQGTTPQISPSTLIGSLRTLELGSESQGASESQAPGEENLLGEA
  AGGQDMADSMLMQGSRGLTDQAIFYAVTPLPWCPHLVAVCPIPAAGLDVTQPCGDCGTIQ
  ENWVCLSCYQVYCGRYINGHMLQHHGNSGHPLVLSYIDLSAWCYYCQAYVHHQALLDVKN
  IAHQNKFGEDMPHPH
• 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. In addition to histones, deacetylates other proteins, such as CTTN, tubulin and SQSTM1. Plays a central role in microtubule-dependent cell motility by mediating deacetylation of tubulin. Required for cilia disassembly; via deacetylation of alpha-tubulin. Promotes deacetylation of CTTN, leading to actin polymerization, promotion of autophagosome-lysosome fusion and completion of autophagy. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer. Promotes odontoblast differentiation following IPO7-mediated nuclear import and subsequent repression of RUNX2 expression. In addition to its protein deacetylase activity, plays a key role in the degradation of misfolded proteins: when misfolded proteins are too abundant to be degraded by the chaperone refolding system and the ubiquitin-proteasome, mediates the transport of misfolded proteins to a cytoplasmic juxtanuclear structure called aggresome. Probably acts as an adapter that recognizes polyubiquitinated misfolded proteins and target them to the aggresome, facilitating their clearance by autophagy.
• KEGG Pathway:
  Neutrophil extracellular trap formation (hsa04613)
  Amyotrophic lateral sclerosis (hsa05014)
  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)
  HSF1 activation (R-HSA-3371511)
  Notch-HLH transcription pathway (R-HSA-350054)
  Cilium Assembly (R-HSA-5617833)
  Transcriptional regulation by RUNX2 (R-HSA-8878166)
  RUNX2 regulates osteoblast differentiation (R-HSA-8940973)
  Chaperone Mediated Autophagy (R-HSA-9613829)
  Late endosomal microautophagy (R-HSA-9615710)
  Aggrephagy (R-HSA-9646399)
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)
• BioCyc Pathway: MetaCyc:HS01799-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
X-linked dominant chondrodysplasia, Chassaing-Lacombe type	DISCW45F	Moderate	X-linked	[1]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Histone deacetylase 6 (HDAC6) decreases the response to substance of Doxorubicin.	[15]
Cisplatin	DMRHGI9	Approved	Histone deacetylase 6 (HDAC6) decreases the response to substance of Cisplatin.	[15]
Bortezomib	DMNO38U	Approved	Histone deacetylase 6 (HDAC6) decreases the response to substance of Bortezomib.	[16]

2 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 6 (HDAC6).	[2]
Marinol	DM70IK5	Approved	Marinol decreases the methylation of Histone deacetylase 6 (HDAC6).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Histone deacetylase 6 (HDAC6).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Histone deacetylase 6 (HDAC6).	[4]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Histone deacetylase 6 (HDAC6).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the activity of Histone deacetylase 6 (HDAC6).	[6]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Histone deacetylase 6 (HDAC6).	[8]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the expression of Histone deacetylase 6 (HDAC6).	[9]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Histone deacetylase 6 (HDAC6).	[9]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Histone deacetylase 6 (HDAC6).	[3]
Rocilinostat	DMSTH01	Phase 2	Rocilinostat decreases the activity of Histone deacetylase 6 (HDAC6).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Histone deacetylase 6 (HDAC6).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Histone deacetylase 6 (HDAC6).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the activity of Histone deacetylase 6 (HDAC6).	[6]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the activity of Histone deacetylase 6 (HDAC6).	[13]
Dibutyl phthalate	DMEDGKO	Investigative	Dibutyl phthalate increases the expression of Histone deacetylase 6 (HDAC6).	[14]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] 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.
• [3] Estrogen down regulates COMT transcription via promoter DNA methylation in human breast cancer cells. Toxicol Appl Pharmacol. 2019 Mar 15;367:12-22.
• [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] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [6] 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.
• [7] Epigenetic activation of O-linked -N-acetylglucosamine transferase overrides the differentiation blockage in acute leukemia. EBioMedicine. 2020 Apr;54:102678. doi: 10.1016/j.ebiom.2020.102678. Epub 2020 Apr 6.
• [8] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [9] 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.
• [10] Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood. 2012 Mar 15;119(11):2579-89. doi: 10.1182/blood-2011-10-387365. Epub 2012 Jan 19.
• [11] 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.
• [12] Bisphenol A-induced epithelial to mesenchymal transition is mediated by cyclooxygenase-2 up-regulation in human endometrial carcinoma cells. Reprod Toxicol. 2015 Dec;58:229-33.
• [13] Sulforaphane destabilizes the androgen receptor in prostate cancer cells by inactivating histone deacetylase 6. Proc Natl Acad Sci U S A. 2009 Sep 29;106(39):16663-8. doi: 10.1073/pnas.0908908106. Epub 2009 Sep 15.
• [14] Phthalates stimulate the epithelial to mesenchymal transition through an HDAC6-dependent mechanism in human breast epithelial stem cells. Toxicol Sci. 2012 Aug;128(2):365-76. doi: 10.1093/toxsci/kfs163. Epub 2012 May 2.
• [15] ERR contributes to HDAC6-induced chemoresistance of osteosarcoma cells. Cell Biol Toxicol. 2023 Jun;39(3):813-825. doi: 10.1007/s10565-021-09651-8. Epub 2021 Sep 15.
• [16] Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells. Cancer Res. 2006 Apr 1;66(7):3773-81. doi: 10.1158/0008-5472.CAN-05-2961.