Details of Drug Off-Target (DOT)

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

• DOT Name: Forkhead box protein N3 (FOXN3)
• Synonyms: Checkpoint suppressor 1
• Gene Name: FOXN3
• Related Disease:
  Breast cancer
  Breast carcinoma
  Pseudotumor cerebri
  Acute myelogenous leukaemia
  Advanced cancer
  B-cell lymphoma
  Bone osteosarcoma
  Chromosomal disorder
  Classic Hodgkin lymphoma
  Colon cancer
  Colon carcinoma
  Gastric neoplasm
  Hepatocellular carcinoma
  Laryngeal carcinoma
  Melanoma
  Multiple endocrine neoplasia type 1
  Neoplasm
  Neuroendocrine neoplasm
  Oral cancer
  Osteosarcoma
  Schizophrenia
  Alopecia
• UniProt ID: FOXN3_HUMAN
• PDB ID: 6NCE; 6NCM
• Pfam ID: PF00250
• Sequence:
  MGPVMPPSKKPESSGISVSSGLSQCYGGSGFSKALQEDDDLDFSLPDIRLEEGAMEDEEL
  TNLNWLHESKNLLKSFGESVLRSVSPVQDLDDDTPPSPAHSDMPYDARQNPNCKPPYSFS
  CLIFMAIEDSPTKRLPVKDIYNWILEHFPYFANAPTGWKNSVRHNLSLNKCFKKVDKERS
  QSIGKGSLWCIDPEYRQNLIQALKKTPYHPHPHVFNTPPTCPQAYQSTSGPPIWPGSTFF
  KRNGALLQDPDIDAASAMMLLNTPPEIQAGFPPGVIQNGARVLSRGLFPGVRPLPITPIG
  VTAAMRNGITSCRMRTESEPSCGSPVVSGDPKEDHNYSSAKSSNARSTSPTSDSISSSSS
  SADDHYEFATKGSQEGSEGSEGSFRSHESPSDTEEDDRKHSQKEPKDSLGDSGYASQHKK
  RQHFAKARKVPSDTLPLKKRRTEKPPESDDEEMKEAAGSLLHLAGIRSCLNNITNRTAKG
  QKEQKETTKN
• Function: Acts as a transcriptional repressor. May be involved in DNA damage-inducible cell cycle arrests (checkpoints).

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Biomarker	[1]
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[1]
Pseudotumor cerebri	DISLLY7S	Definitive	Genetic Variation	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[5]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[5]
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[6]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Altered Expression	[7]
Colon cancer	DISVC52G	Strong	Biomarker	[8]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[8]
Gastric neoplasm	DISOKN4Y	Strong	Altered Expression	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Laryngeal carcinoma	DISNHCIV	Strong	Biomarker	[10]
Melanoma	DIS1RRCY	Strong	Genetic Variation	[1]
Multiple endocrine neoplasia type 1	DIS0RJRK	Strong	Genetic Variation	[11]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Neuroendocrine neoplasm	DISNPLOO	Strong	Genetic Variation	[11]
Oral cancer	DISLD42D	Strong	Altered Expression	[12]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[5]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[13]
Alopecia	DIS37HU4	moderate	Altered Expression	[14]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Forkhead box protein N3 (FOXN3) affects the response to substance of Methotrexate.	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Forkhead box protein N3 (FOXN3).	[15]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Forkhead box protein N3 (FOXN3).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Forkhead box protein N3 (FOXN3).	[31]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Forkhead box protein N3 (FOXN3).	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Forkhead box protein N3 (FOXN3).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Forkhead box protein N3 (FOXN3).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Forkhead box protein N3 (FOXN3).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Forkhead box protein N3 (FOXN3).	[19]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Forkhead box protein N3 (FOXN3).	[20]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Forkhead box protein N3 (FOXN3).	[22]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Forkhead box protein N3 (FOXN3).	[23]
Marinol	DM70IK5	Approved	Marinol increases the expression of Forkhead box protein N3 (FOXN3).	[24]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Forkhead box protein N3 (FOXN3).	[25]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Forkhead box protein N3 (FOXN3).	[26]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Forkhead box protein N3 (FOXN3).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Forkhead box protein N3 (FOXN3).	[28]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Forkhead box protein N3 (FOXN3).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Forkhead box protein N3 (FOXN3).	[30]

References

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• [2] Genetic Survey of Adult-Onset Idiopathic Intracranial Hypertension.J Neuroophthalmol. 2019 Mar;39(1):50-55. doi: 10.1097/WNO.0000000000000648.
• [3] Novel tumor-suppressor FOXN3 is downregulated in adult acute myeloid leukemia.Oncol Lett. 2019 Aug;18(2):1521-1529. doi: 10.3892/ol.2019.10424. Epub 2019 May 31.
• [4] Checkpoint suppressor 1 suppresses transcriptional activity of ER and breast cancer cell proliferation via deacetylase SIRT1.Cell Death Dis. 2018 May 1;9(5):559. doi: 10.1038/s41419-018-0629-3.
• [5] FOXN3 is downregulated in osteosarcoma and transcriptionally regulates SIRT6, and suppresses migration and invasion in osteosarcoma.Oncol Rep. 2019 Feb;41(2):1404-1414. doi: 10.3892/or.2018.6878. Epub 2018 Nov 21.
• [6] Foxn3 is essential for craniofacial development in mice and a putative candidate involved in human congenital craniofacial defects.Biochem Biophys Res Commun. 2010 Sep 10;400(1):60-5. doi: 10.1016/j.bbrc.2010.07.142. Epub 2010 Aug 5.
• [7] Deregulated FOX genes in Hodgkin lymphoma.Genes Chromosomes Cancer. 2014 Nov;53(11):917-33. doi: 10.1002/gcc.22204. Epub 2014 Jul 17.
• [8] Loss of FOXN3 in colon cancer activates beta-catenin/TCF signaling and promotes the growth and migration of cancer cells.Oncotarget. 2017 Feb 7;8(6):9783-9793. doi: 10.18632/oncotarget.14189.
• [9] Interleukin 1 Up-regulates MicroRNA 135b to Promote Inflammation-Associated Gastric Carcinogenesis in Mice.Gastroenterology. 2019 Mar;156(4):1140-1155.e4. doi: 10.1053/j.gastro.2018.11.059. Epub 2018 Nov 30.
• [10] Metal-proteinase ADAM12, kinesin 14 and checkpoint suppressor 1 as new molecular markers of laryngeal carcinoma.Eur Arch Otorhinolaryngol. 2009 Oct;266(10):1501-7. doi: 10.1007/s00405-009-1019-3. Epub 2009 Jul 16.
• [11] Higher risk of aggressive pancreatic neuroendocrine tumors in MEN1 patients with MEN1 mutations affecting the CHES1 interacting MENIN domain.J Clin Endocrinol Metab. 2014 Nov;99(11):E2387-91. doi: 10.1210/jc.2013-4432. Epub 2014 Sep 11.
• [12] Identification of differentially expressed genes in oral squamous cell carcinoma (OSCC): overexpression of NPM, CDK1 and NDRG1 and underexpression of CHES1.Int J Cancer. 2005 May 10;114(6):942-9. doi: 10.1002/ijc.20663.
• [13] Genome-wide association study identifies five new schizophrenia loci.Nat Genet. 2011 Sep 18;43(10):969-76. doi: 10.1038/ng.940.
• [14] 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.
• [15] 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.
• [16] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [17] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [18] 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.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [21] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [22] 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.
• [23] 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.
• [24] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [25] Dissecting progressive stages of 5-fluorouracil resistance in vitro using RNA expression profiling. Int J Cancer. 2004 Nov 1;112(2):200-12. doi: 10.1002/ijc.20401.
• [26] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [27] Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. Int J Cancer. 2003 Mar 20;104(2):204-12.
• [28] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [29] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [30] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [31] 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.
• [32] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [33] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.