Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE80D6I)

• DOT Name: Forkhead box protein N1 (FOXN1)
• Synonyms: Winged-helix transcription factor nude
• Gene Name: FOXN1
• Related Disease:
  T-cell immunodeficiency, congenital alopecia, and nail dystrophy
  Alopecia
  Anencephaly
  Autism spectrum disorder
  Breast neoplasm
  CHARGE syndrome
  Congenital alopecia
  DiGeorge syndrome
  Epithelial neoplasm
  Hepatocellular carcinoma
  Hypertrichosis lanuginosa congenita
  Neoplasm
  Neural tube defect
  Non-small-cell lung cancer
  Pneumonia
  Pneumonitis
  Severe combined immunodeficiency
  Shprintzen-Goldberg syndrome
  Skin cancer
  Squamous cell carcinoma
  T-cell acute lymphoblastic leukaemia
  T-cell leukaemia
  T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominant
  Adult glioblastoma
  Glioblastoma multiforme
  High blood pressure
  Advanced cancer
• UniProt ID: FOXN1_HUMAN
• PDB ID: 5OCN; 6EL8
• Pfam ID: PF00250
• Sequence:
  MVSLPPPQSDVTLPGPTRLEGERQGDLMQAPGLPGSPAPQSKHAGFSCSSFVSDGPPERT
  PSLPPHSPRIASPGPEQVQGHCPAGPGPGPFRLSPSDKYPGFGFEEAAASSPGRFLKGSH
  APFHPYKRPFHEDVFPEAETTLALKGHSFKTPGPLEAFEEIPVDVAEAEAFLPGFSAEAW
  CNGLPYPSQEHGPQVLGSEVKVKPPVLESGAGMFCYQPPLQHMYCSSQPPFHQYSPGGGS
  YPIPYLGSSHYQYQRMAPQASTDGHQPLFPKPIYSYSILIFMALKNSKTGSLPVSEIYNF
  MTEHFPYFKTAPDGWKNSVRHNLSLNKCFEKVENKSGSSSRKGCLWALNPAKIDKMQEEL
  QKWKRKDPIAVRKSMAKPEELDSLIGDKREKLGSPLLGCPPPGLSGSGPIRPLAPPAGLS
  PPLHSLHPAPGPIPGKNPLQDLLMGHTPSCYGQTYLHLSPGLAPPGPPQPLFPQPDGHLE
  LRAQPGTPQDSPLPAHTPPSHSAKLLAEPSPARTMHDTLLPDGDLGTDLDAINPSLTDFD
  FQGNLWEQLKDDSLALDPLVLVTSSPTSSSMPPPQPPPHCFPPGPCLTETGSGAGDLAAP
  GSGGSGALGDLHLTTLYSAFMELEPTPPTAPAGPSVYLSPSSKPVALA
• Function: Transcriptional regulator which regulates the development, differentiation, and function of thymic epithelial cells (TECs) both in the prenatal and postnatal thymus. Acts as a master regulator of the TECs lineage development and is required from the onset of differentiation in progenitor TECs in the developing fetus to the final differentiation steps through which TECs mature to acquire their full functionality. Regulates, either directly or indirectly the expression of a variety of genes that mediate diverse aspects of thymus development and function, including MHC Class II, DLL4, CCL25, CTSL, CD40 and PAX1. Regulates the differentiation of the immature TECs into functional cortical TECs (cTECs) and medullary TECs (mTECs). Essential for maintenance of mTECs population in the postnatal thymus. Involved in the morphogenesis and maintenance of the three-dimensional thymic microstructure which is necessary for a fully functional thymus. Plays an important role in the maintenance of hematopoiesis and particularly T lineage progenitors within the bone marrow niche with age. Essential for the vascularization of the thymus anlage. Promotes the terminal differentiation of epithelial cells in the epidermis and hair follicles, partly by negatively regulating the activity of protein kinase C. Plays a crucial role in the early prenatal stages of T-cell ontogeny.
• Tissue Specificity: Expressed in thymus.

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
T-cell immunodeficiency, congenital alopecia, and nail dystrophy	DIS25UA0	Definitive	Semidominant	[1]
Alopecia	DIS37HU4	Strong	Genetic Variation	[2]
Anencephaly	DISIYW6T	Strong	Genetic Variation	[3]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[5]
CHARGE syndrome	DISKD3CW	Strong	Altered Expression	[6]
Congenital alopecia	DIS1LDG6	Strong	Genetic Variation	[3]
DiGeorge syndrome	DIST1RKO	Strong	Genetic Variation	[7]
Epithelial neoplasm	DIS0T594	Strong	Biomarker	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[9]
Hypertrichosis lanuginosa congenita	DISX1C1I	Strong	Genetic Variation	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Neural tube defect	DIS5J95E	Strong	Genetic Variation	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[11]
Pneumonia	DIS8EF3M	Strong	Biomarker	[12]
Pneumonitis	DIS88E0K	Strong	Biomarker	[12]
Severe combined immunodeficiency	DIS6MF4Q	Strong	Genetic Variation	[13]
Shprintzen-Goldberg syndrome	DISQH6P3	Strong	Genetic Variation	[7]
Skin cancer	DISTM18U	Strong	Biomarker	[14]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[15]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Genetic Variation	[16]
T-cell leukaemia	DISJ6YIF	Strong	Biomarker	[16]
T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominant	DISK1L7Q	Strong	Autosomal dominant	[17]
Adult glioblastoma	DISVP4LU	moderate	Biomarker	[18]
Glioblastoma multiforme	DISK8246	moderate	Biomarker	[18]
High blood pressure	DISY2OHH	moderate	Altered Expression	[19]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[11]

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 Forkhead box protein N1 (FOXN1).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Forkhead box protein N1 (FOXN1).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Forkhead box protein N1 (FOXN1).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of Forkhead box protein N1 (FOXN1).	[23]
U0126	DM31OGF	Investigative	U0126 increases the expression of Forkhead box protein N1 (FOXN1).	[24]

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] Taking advantage from phenotype variability in a local animal genetic resource: identification of genomic regions associated with the hairless phenotype in Casertana pigs.Anim Genet. 2018 Aug;49(4):321-325. doi: 10.1111/age.12665. Epub 2018 Apr 19.
• [3] FOXN1 homozygous mutation associated with anencephaly and severe neural tube defect in human athymic Nude/SCID fetus.Clin Genet. 2008 Apr;73(4):380-4. doi: 10.1111/j.1399-0004.2008.00977.x.
• [4] Whole-Exome Sequencing in a South American Cohort Links ALDH1A3, FOXN1 and Retinoic Acid Regulation Pathways to Autism Spectrum Disorders.PLoS One. 2015 Sep 9;10(9):e0135927. doi: 10.1371/journal.pone.0135927. eCollection 2015.
• [5] Cyclooxygenase-2 directly induces MCF-7 breast tumor cells to develop into exponentially growing, highly angiogenic and regionally invasive human ductal carcinoma xenografts.Anticancer Res. 2007 Mar-Apr;27(2):719-27.
• [6] Chd7 Is Critical for Early T-Cell Development and Thymus Organogenesis in Zebrafish.Am J Pathol. 2018 Apr;188(4):1043-1058. doi: 10.1016/j.ajpath.2017.12.005. Epub 2018 Jan 31.
• [7] Recurrent microdeletions at chromosome 2p11.2 are associated with thymic hypoplasia and features resembling DiGeorge syndrome.J Allergy Clin Immunol. 2020 Jan;145(1):358-367.e2. doi: 10.1016/j.jaci.2019.09.020. Epub 2019 Oct 7.
• [8] FOXN1 Transcription Factor in Epithelial Growth and Wound Healing.Mol Cell Biol. 2017 Aug 11;37(17):e00110-17. doi: 10.1128/MCB.00110-17. Print 2017 Sep 1.
• [9] Genome-wide association analysis identifies a GLUL haplotype for familial hepatitis B virus-related hepatocellular carcinoma.Cancer. 2017 Oct 15;123(20):3966-3976. doi: 10.1002/cncr.30851. Epub 2017 Jun 29.
• [10] FOXN1 Duplication and Congenital Hypertrichosis.Pediatr Dermatol. 2017 Mar;34(2):e77-e79. doi: 10.1111/pde.13078.
• [11] Forkhead box N1 inhibits the progression of non-small cell lung cancer and serves as a tumor suppressor.Oncol Lett. 2018 May;15(5):7221-7230. doi: 10.3892/ol.2018.8210. Epub 2018 Mar 8.
• [12] Memory-type ST2(+)CD4(+) T cells participate in the steroid-resistant pathology of eosinophilic pneumonia.Sci Rep. 2017 Jul 28;7(1):6805. doi: 10.1038/s41598-017-06962-x.
• [13] FOXN1 compound heterozygous mutations cause selective thymic hypoplasia in humans.J Clin Invest. 2019 Nov 1;129(11):4724-4738. doi: 10.1172/JCI127565.
• [14] A positive FGFR3/FOXN1 feedback loop underlies benign skin keratosis versus squamous cell carcinoma formation in humans.J Clin Invest. 2009 Oct;119(10):3127-37. doi: 10.1172/JCI38543.
• [15] Thymic carcinoma: is it a separate entity? From molecular to clinical evidence.Thorac Surg Clin. 2011 Feb;21(1):25-31. v-vi. doi: 10.1016/j.thorsurg.2010.08.010.
• [16] FoxN1-dependent thymic epithelial cells promote T-cell leukemia development.Carcinogenesis. 2018 Dec 31;39(12):1463-1476. doi: 10.1093/carcin/bgy127.
• [17] Ancestral founder mutation of the nude (FOXN1) gene in congenital severe combined immunodeficiency associated with alopecia in southern Italy population. Ann Hum Genet. 2004 May;68(Pt 3):265-8. doi: 10.1046/j.1529-8817.2004.00091.x.
• [18] Targeted Treatment of Experimental Spinal Cord Glioma With Dual Gene-Engineered Human Neural Stem Cells.Neurosurgery. 2016 Sep;79(3):481-91. doi: 10.1227/NEU.0000000000001174.
• [19] Mechanisms in hypertension and target organ damage: Is the role of the thymus key? (Review).Int J Mol Med. 2018 Jul;42(1):3-12. doi: 10.3892/ijmm.2018.3605. Epub 2018 Mar 30.
• [20] 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.
• [21] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [22] 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.
• [23] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [24] Arsenite suppression of BMP signaling in human keratinocytes. Toxicol Appl Pharmacol. 2013 Jun 15;269(3):290-6. doi: 10.1016/j.taap.2013.02.017. Epub 2013 Apr 6.