Details of Drug Off-Target (DOT)

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

• DOT Name: Transcription factor HES-4 (HES4)
• Synonyms: hHES4; Class B basic helix-loop-helix protein 42; bHLHb42; Hairy and enhancer of split 4; bHLH factor Hes4
• Gene Name: HES4
• Related Disease:
  Ependymoma
  Clear cell renal carcinoma
  Huntington disease
  Neuroblastoma
  Bone osteosarcoma
  Neoplasm
  Osteosarcoma
• UniProt ID: HES4_HUMAN
• Pfam ID: PF07527 ; PF00010
• Sequence:
  MAADTPGKPSASPMAGAPASASRTPDKPRSAAEHRKSSKPVMEKRRRARINESLAQLKTL
  ILDALRKESSRHSKLEKADILEMTVRHLRSLRRVQVTAALSADPAVLGKYRAGFHECLAE
  VNRFLAGCEGVPADVRSRLLGHLAACLRQLGPSRRPASLSPAAPAEAPAPEVYAGRPLLP
  SLGGPFPLLAPPLLPGLTRALPAAPRAGPQGPGGPWRPWLR
• Function: Transcriptional repressor. Binds DNA on N-box motifs: 5'-CACNAG-3'.
• KEGG Pathway: Human papillomavirus infection (hsa05165)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ependymoma	DISUMRNZ	Definitive	Altered Expression	[1]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[2]
Huntington disease	DISQPLA4	Strong	Biomarker	[3]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[3]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[4]
Neoplasm	DISZKGEW	Limited	Altered Expression	[4]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[4]

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 Transcription factor HES-4 (HES4).	[5]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Transcription factor HES-4 (HES4).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Transcription factor HES-4 (HES4).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Transcription factor HES-4 (HES4).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Transcription factor HES-4 (HES4).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Transcription factor HES-4 (HES4).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Transcription factor HES-4 (HES4).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Transcription factor HES-4 (HES4).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Transcription factor HES-4 (HES4).	[11]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Transcription factor HES-4 (HES4).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Transcription factor HES-4 (HES4).	[13]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Transcription factor HES-4 (HES4).	[14]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Transcription factor HES-4 (HES4).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Transcription factor HES-4 (HES4).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Transcription factor HES-4 (HES4).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transcription factor HES-4 (HES4).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Transcription factor HES-4 (HES4).	[19]

References

• [1] Notch pathway in ependymoma RELA-fused subgroup: upregulation and association with cancer stem cells markers expression.Cancer Gene Ther. 2020 Jun;27(6):509-512. doi: 10.1038/s41417-019-0122-x. Epub 2019 Jul 16.
• [2] Predictive values of Notch signalling in renal carcinoma.Arch Med Sci. 2017 Oct;13(6):1249-1254. doi: 10.5114/aoms.2017.65649. Epub 2017 Jan 31.
• [3] Epigenetic dysregulation of hairy and enhancer of split 4 (HES4) is associated with striatal degeneration in postmortem Huntington brains.Hum Mol Genet. 2015 Mar 1;24(5):1441-56. doi: 10.1093/hmg/ddu561. Epub 2014 Dec 5.
• [4] Hes4: A potential prognostic biomarker for newly diagnosed patients with high-grade osteosarcoma.Pediatr Blood Cancer. 2017 May;64(5):10.1002/pbc.26318. doi: 10.1002/pbc.26318. Epub 2016 Oct 27.
• [5] 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.
• [6] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [7] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [8] 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.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [11] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [14] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [15] 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.
• [16] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] 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.
• [19] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.