Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN7BH79)

• DOT Name: Hairy/enhancer-of-split related with YRPW motif-like protein (HEYL)
• Synonyms: hHeyL; Class B basic helix-loop-helix protein 33; bHLHb33; Hairy-related transcription factor 3; HRT-3; hHRT3
• Gene Name: HEYL
• Related Disease:
  Mycoses
  OPTN-related open angle glaucoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colorectal carcinoma
  Fungal keratitis
  Glaucoma/ocular hypertension
  Metastatic malignant neoplasm
  Neoplasm
  Non-small-cell lung cancer
  Sjogren syndrome
  Prostate cancer
  Prostate carcinoma
• UniProt ID: HEYL_HUMAN
• Pfam ID: PF07527 ; PF00010
• Sequence:
  MKRPKEPSGSDGESDGPIDVGQEGQLSQMARPLSTPSSSQMQARKKHRGIIEKRRRDRIN
  SSLSELRRLVPTAFEKQGSSKLEKAEVLQMTVDHLKMLHATGGTGFFDARALAVDFRSIG
  FRECLTEVIRYLGVLEGPSSRADPVRIRLLSHLNSYAAEMEPSPTPTGPLAFPAWPWSFF
  HSCPGLPALSNQLAILGRVPSPVLPGVSSPAYPIPALRTAPLRRATGIILPARRNVLPSR
  GASSTRRARPLERPATPVPVAPSSRAARSSHIAPLLQSSSPTPPGPTGSAAYVAVPTPNS
  SSPGPAGRPAGAMLYHSWVSEITEIGAF
• Function: Downstream effector of Notch signaling which may be required for cardiovascular development. Transcriptional repressor which binds preferentially to the canonical E box sequence 5'-CACGTG-3'. Represses transcription by the cardiac transcriptional activators GATA4 and GATA6.
• KEGG Pathway:
  Notch sig.ling pathway (hsa04330)
  Human papillomavirus infection (hsa05165)
  Pathways in cancer (hsa05200)
  Breast cancer (hsa05224)
• Reactome Pathway:
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  NOTCH3 Intracellular Domain Regulates Transcription (R-HSA-9013508)
  Regulation of CDH11 gene transcription (R-HSA-9762293)
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mycoses	DIS9K7PB	Definitive	Genetic Variation	[1]
OPTN-related open angle glaucoma	DISDR98A	Definitive	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[3]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[5]
Fungal keratitis	DISA0XP5	Strong	Biomarker	[6]
Glaucoma/ocular hypertension	DISLBXBY	Strong	Genetic Variation	[7]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[8]
Sjogren syndrome	DISUBX7H	Strong	Biomarker	[9]
Prostate cancer	DISF190Y	moderate	Biomarker	[10]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Hairy/enhancer-of-split related with YRPW motif-like protein (HEYL).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Hairy/enhancer-of-split related with YRPW motif-like protein (HEYL).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Hairy/enhancer-of-split related with YRPW motif-like protein (HEYL).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Hairy/enhancer-of-split related with YRPW motif-like protein (HEYL).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Hairy/enhancer-of-split related with YRPW motif-like protein (HEYL).	[15]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Hairy/enhancer-of-split related with YRPW motif-like protein (HEYL).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Hairy/enhancer-of-split related with YRPW motif-like protein (HEYL).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Hairy/enhancer-of-split related with YRPW motif-like protein (HEYL).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Hairy/enhancer-of-split related with YRPW motif-like protein (HEYL).	[18]

References

• [1] InVivo Confocal Microscopy Cellular Features of Host and Organism in Bacterial, Fungal, and Acanthamoeba Keratitis.Am J Ophthalmol. 2018 Jun;190:24-33. doi: 10.1016/j.ajo.2018.03.010. Epub 2018 Mar 14.
• [2] Funduscopic versus HRT III Confocal Scanner Vertical Cup-Disc Ratio Assessment in Normal Tension and Primary Open Angle Glaucoma (The Leuven Eye Study).Ophthalmic Res. 2017;57(2):100-106. doi: 10.1159/000446659. Epub 2016 Aug 4.
• [3] Total polyphenol intake and breast cancer risk in the Seguimiento Universidad de Navarra (SUN) cohort.Br J Nutr. 2019 Sep 14;122(5):542-551. doi: 10.1017/S0007114518003811. Epub 2019 Feb 12.
• [4] Inhibition of Notch signaling reduces the stem-like population of breast cancer cells and prevents mammosphere formation.Anticancer Res. 2010 Oct;30(10):3853-67.
• [5] The notch target gene HEYL modulates metastasis forming capacity of colorectal cancer patient-derived spheroid cells in vivo.BMC Cancer. 2019 Dec 3;19(1):1181. doi: 10.1186/s12885-019-6396-4.
• [6] Cellular morphological changes detected by laser scanning in vivo confocal microscopy associated with clinical outcome in fungal keratitis.Sci Rep. 2019 Jun 6;9(1):8334. doi: 10.1038/s41598-019-44833-9.
• [7] Diagnostic accuracy of macular ganglion cell-inner plexiform layer thickness for glaucoma detection in a population-based study: Comparison with optic nerve head imaging parameters.PLoS One. 2018 Jun 26;13(6):e0199134. doi: 10.1371/journal.pone.0199134. eCollection 2018.
• [8] Polymorphisms in Epithelial-Mesenchymal Transition-Related Genes and the Prognosis of Surgically Treated Non-small Cell Lung Cancer.Ann Surg Oncol. 2017 Oct;24(11):3386-3395. doi: 10.1245/s10434-017-6002-4. Epub 2017 Aug 1.
• [9] Evaluation of the corneal epithelium in non-Sjgren's and Sjgren's dry eyes: an in vivo confocal microscopy study using HRT III RCM.BMC Ophthalmol. 2018 Dec 4;18(1):309. doi: 10.1186/s12886-018-0971-3.
• [10] Repression of androgen receptor activity by HEYL, a third member of the Hairy/Enhancer-of-split-related family of Notch effectors.J Biol Chem. 2011 May 20;286(20):17796-808. doi: 10.1074/jbc.M110.198655. Epub 2011 Mar 17.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] 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.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] 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.
• [15] 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.
• [16] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [17] 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.
• [18] 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.
• [19] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.