Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAQD3YV)

• DOT Name: Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2)
• Synonyms: ARNT protein 2; Class E basic helix-loop-helix protein 1; bHLHe1
• Gene Name: ARNT2
• Related Disease:
  Autism spectrum disorder
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cryptorchidism
  Gastric cancer
  Hepatocellular carcinoma
  Hypopituitarism
  Hypospadias
  Kallmann syndrome
  Multiple sclerosis
  Neoplasm
  Nervous system inflammation
  Non-small-cell lung cancer
  Obesity
  Schizophrenia
  Stomach cancer
  Webb-Dattani syndrome
  Atrial fibrillation
  Familial atrial fibrillation
  Hirschsprung disease
  Neuroblastoma
  Septooptic dysplasia
  Adult glioblastoma
  Glioblastoma multiforme
• UniProt ID: ARNT2_HUMAN
• Pfam ID: PF00010 ; PF00989 ; PF14598
• Sequence:
  MATPAAVNPPEMASDIPGSVTLPVAPMAATGQVRMAGAMPARGGKRRSGMDFDDEDGEGP
  SKFSRENHSEIERRRRNKMTQYITELSDMVPTCSALARKPDKLTILRMAVSHMKSMRGTG
  NKSTDGAYKPSFLTEQELKHLILEAADGFLFVVAAETGRVIYVSDSVTPVLNQPQSEWFG
  STLYEQVHPDDVEKLREQLCTSENSMTGRILDLKTGTVKKEGQQSSMRMCMGSRRSFICR
  MRCGNAPLDHLPLNRITTMRKRFRNGLGPVKEGEAQYAVVHCTGYIKAWPPAGMTIPEED
  ADVGQGSKYCLVAIGRLQVTSSPVCMDMNGMSVPTEFLSRHNSDGIITFVDPRCISVIGY
  QPQDLLGKDILEFCHPEDQSHLRESFQQVVKLKGQVLSVMYRFRTKNREWMLIRTSSFTF
  QNPYSDEIEYIICTNTNVKQLQQQQAELEVHQRDGLSSYDLSQVPVPNLPAGVHEAGKSV
  EKADAIFSQERDPRFAEMFAGISASEKKMMSSASAAGTQQIYSQGSPFPSGHSGKAFSSS
  VVHVPGVNDIQSSSSTGQNMSQISRQLNQSQVAWTGSRPPFPGQQIPSQSSKTQSSPFGI
  GTSHTYPADPSSYSPLSSPATSSPSGNAYSSLANRTPGFAESGQSSGQFQGRPSEVWSQW
  QSQHHGQQSGEQHSHQQPGQTEVFQDMLPMPGDPTQGTGNYNIEDFADLGMFPPFSE
• Function: Transcription factor that plays a role in the development of the hypothalamo-pituitary axis, postnatal brain growth, and visual and renal function. Specifically recognizes the xenobiotic response element (XRE).
• KEGG Pathway:
  Pathways in cancer (hsa05200)
  Transcriptio.l misregulation in cancer (hsa05202)
  Re.l cell carcinoma (hsa05211)
• Reactome Pathway:
  Phase I - Functionalization of compounds (R-HSA-211945)
  Endogenous sterols (R-HSA-211976)
  Xenobiotics (R-HSA-211981)
  Aryl hydrocarbon receptor signalling (R-HSA-8937144)
  NPAS4 regulates expression of target genes (R-HSA-9768919)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[3]
Cryptorchidism	DISYUD2P	Strong	Genetic Variation	[4]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
Hypopituitarism	DIS1QT3G	Strong	Biomarker	[7]
Hypospadias	DIS48CCP	Strong	Genetic Variation	[8]
Kallmann syndrome	DISO3HDG	Strong	GermlineCausalMutation	[7]
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Nervous system inflammation	DISB3X5A	Strong	Biomarker	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[10]
Obesity	DIS47Y1K	Strong	Biomarker	[11]
Schizophrenia	DISSRV2N	Strong	Biomarker	[1]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[5]
Webb-Dattani syndrome	DISXXXWT	Strong	Autosomal recessive	[12]
Atrial fibrillation	DIS15W6U	moderate	Biomarker	[13]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[13]
Hirschsprung disease	DISUUSM1	moderate	Altered Expression	[14]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[14]
Septooptic dysplasia	DISXYR1H	Supportive	Autosomal dominant	[7]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[15]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[15]

21 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 Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2).	[20]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2).	[21]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2).	[22]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2).	[23]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2).	[24]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2).	[23]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2).	[21]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2).	[25]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2).	[26]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2).	[27]
Isoproterenol	DMK7MEY	Approved	Isoproterenol decreases the expression of Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2).	[28]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2).	[23]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2).	[29]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2).	[32]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2).	[33]

1 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 Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2).	[30]

References

• [1] Heat shock alters the expression of schizophrenia and autism candidate genes in an induced pluripotent stem cell model of the human telencephalon.PLoS One. 2014 Apr 15;9(4):e94968. doi: 10.1371/journal.pone.0094968. eCollection 2014.
• [2] siRNA-mediated knockdown of aryl hydrocarbon receptor nuclear translocator 2 affects hypoxia-inducible factor-1 regulatory signaling and metabolism in human breast cancer cells.FEBS Lett. 2011 Oct 20;585(20):3310-5. doi: 10.1016/j.febslet.2011.09.017. Epub 2011 Sep 19.
• [3] Drug metabolism-related genes as potential biomarkers: analysis of expression in normal and tumour breast tissue.Breast Cancer Res Treat. 2008 Aug;110(3):521-30. doi: 10.1007/s10549-007-9739-9. Epub 2007 Sep 27.
• [4] Association of variants in genes involved in environmental chemical metabolism and risk of cryptorchidism and hypospadias.J Hum Genet. 2012 Jul;57(7):434-41. doi: 10.1038/jhg.2012.48. Epub 2012 May 31.
• [5] Overexpression of ARNT2 is associated with decreased cell proliferation and better prognosis in gastric cancer.Mol Cell Biochem. 2019 Jan;450(1-2):97-103. doi: 10.1007/s11010-018-3376-y. Epub 2018 Jun 12.
• [6] Downregulation of ARNT2 promotes tumor growth and predicts poor prognosis in human hepatocellular carcinoma.J Gastroenterol Hepatol. 2015 Jun;30(6):1085-93. doi: 10.1111/jgh.12905.
• [7] ARNT2 mutation causes hypopituitarism, post-natal microcephaly, visual and renal anomalies. Brain. 2013 Oct;136(Pt 10):3096-105. doi: 10.1093/brain/awt218. Epub 2013 Sep 10.
• [8] Individual variation of the genetic response to bisphenol a in human foreskin fibroblast cells derived from cryptorchidism and hypospadias patients.PLoS One. 2012;7(12):e52756. doi: 10.1371/journal.pone.0052756. Epub 2012 Dec 28.
• [9] Expression of the neuroprotective protein aryl hydrocarbon receptor nuclear translocator 2 correlates with neuronal stress and disability in models of multiple sclerosis.J Neuroinflammation. 2018 Sep 19;15(1):270. doi: 10.1186/s12974-018-1290-6.
• [10] ARNT2 is downregulated and serves as a potential tumor suppressor gene in non-small cell lung cancer.Tumour Biol. 2015 Mar;36(3):2111-9. doi: 10.1007/s13277-014-2820-1. Epub 2015 Jan 23.
• [11] A viable hypomorphic Arnt2 mutation causes hyperphagic obesity, diabetes and hepatic steatosis.Dis Model Mech. 2018 Dec 18;11(12):dmm035451. doi: 10.1242/dmm.035451.
• [12] Targeted mutation of the murine arylhydrocarbon receptor nuclear translocator 2 (Arnt2) gene reveals partial redundancy with Arnt. Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6692-7. doi: 10.1073/pnas.121494298. Epub 2001 May 29.
• [13] Biobank-driven genomic discovery yields new insight into atrial fibrillation biology.Nat Genet. 2018 Sep;50(9):1234-1239. doi: 10.1038/s41588-018-0171-3. Epub 2018 Jul 30.
• [14] Variants in RET associated with Hirschsprung's disease affect binding of transcription factors and gene expression.Gastroenterology. 2011 Feb;140(2):572-582.e2. doi: 10.1053/j.gastro.2010.10.044. Epub 2010 Oct 25.
• [15] Changes in chromatin state reveal ARNT2 at a node of a tumorigenic transcription factor signature driving glioblastoma cell aggressiveness.Acta Neuropathol. 2018 Feb;135(2):267-283. doi: 10.1007/s00401-017-1783-x. Epub 2017 Nov 17.
• [16] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [17] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [18] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [19] 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.
• [20] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [21] Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells. J Cell Biochem. 2006 Aug 1;98(5):1163-84.
• [22] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [23] 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.
• [24] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [25] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [26] 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.
• [27] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [28] Isoproterenol effects evaluated in heart slices of human and rat in comparison to rat heart in vivo. Toxicol Appl Pharmacol. 2014 Jan 15;274(2):302-12.
• [29] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [30] 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.
• [31] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [32] Xenoestrogens down-regulate aryl-hydrocarbon receptor nuclear translocator 2 mRNA expression in human breast cancer cells via an estrogen receptor alpha-dependent mechanism. Toxicol Lett. 2011 Oct 10;206(2):152-7. doi: 10.1016/j.toxlet.2011.07.007. Epub 2011 Jul 12.
• [33] 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.